Intravenous administration of tramadol

ABSTRACT

A method of treating pain, e.g., acute post-operative pain, by administering to a human patient(s) a therapeutically effective dose of tramadol intravenously in a dosing regimen which includes one or more loading doses administered at shortened intervals as compared to dosing at steady-state is disclosed. In certain embodiments, the dose of tramadol about 25 mg and the second (and optionally) third doses are intravenously administered at intervals of about 2 hours, and thereafter the tramadol is intravenously administered at a dosing interval of about 4 hours, until the patient no longer requires treatment with tramadol.

This application claims the benefit of U.S. Provisional PatentApplication No. 62/356,655, filed Jun. 30, 2016, the disclosures ofwhich are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Tramadol is a centrally acting synthetic analgesic with a dual mechanismof action attributed to the racemic form of the drug, comprised ofμ-opioid activity (binding to μ-opioid receptors and monoamine(serotonin and noradrenalin) reuptake inhibition. Tramadol is an analogof the phenanthrene group of opium alkaloids, which includes morphineand codeine, and is structurally related to these opioids (Grond S andSlabotzi A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43:879-923). Like codeine, there is a substitution of the methyl groupon the phenol ring that imparts a relatively weak affinity for opioidreceptors. (+)-Tramadol is a more potent inhibitor of serotonin uptake,while (−)-tramadol is a more potent inhibitor of norepinephrine uptake.The opioid-like activity of tramadol derives from low affinity bindingof the parent compound to μ-opioid receptors and higher affinity bindingof its main metabolite. Tramadol affinity to μ opioid receptors is about10 times weaker than codeine 60 times weaker than dextropropoxyphene and6,000 times weaker than morphine. The active metaboliteO-desmethyltramadol (M1) possesses a higher affinity to the μ opioidreceptor than tramadol and displays analgesic activity (Leppert W,2009).

Tramadol was originally developed by the German pharmaceutical companyGrünenthal GmbH in the late 1970s and is marketed globally under thetrade names TRAMAL® and others outside of the United States. Theapproved doses of tramadol are 50 mg or 100 mg administered as a slowinjection every 4-6 hours (Tramadol Core Product Label, 2008). In theU.S., tramadol is approved by the Food and Drug Administration (FDA) andmarketed as an oral capsule/tablet for moderate to moderately severepain in adults. Tramadol was first approved in the US in April 1995under the trade name, ULTRAM® (Ortho-McNeil-Janssen Pharmaceuticals,Inc). Tramadol is also an active agent in an extended release product,Ultram® ER, and a combination product with acetaminophen, ULTRACET®. Inthe US, tramadol is only available as immediate release tablets orextended release tablets. Other tramadol formulations approved inseveral countries include tablets, capsules, effervescent powders, andsuppositories (Grond and Sablotzki, 2004; Rosenberg, 2009). The approvedintravenous regimen in India is an initial injection of 50 mg infusionover 2-3 min, followed by 50 mg every 10-20 minutes if necessary up to250 mg for the first hour. Maintenance doses are 50-100 mg every 4-6hours with a maximum dose of 600 mg daily (Tramadol, CIMS Data_India).

Postoperative pain management with tramadol has effectively utilized avariety of delivery methods, including bolus injection (IV or IM),continuous infusions and patient controlled analgesia (PCA) pumps, andvarious combinations of these methods (Scott and Perry, 2000; Grond andSablotzki, 2004). The potency ratio of IV tramadol to IV morphine isapproximately 1:10, while the ratio for IV fentanyl is 1:979 (Grond andSablotzki, 2004).

The “on-demand” analgesic efficacy of tramadol was compared to morphinein the 24-hour post-operative period for 523 patients undergoingabdominal surgery (Vickers M D, Paravicini D. Comparison of tramadolwith morphine for post-operative pain following abdominal surgery. Eur JAnesthesiol. 1995; 12: 265-71). Patients who reported post-operativepain received an initial dose (either tramadol 100 mg or morphine 5 mgi.v.) and, if necessary, repeat i.v. or i.m. doses of tramadol 50 mg ormorphine 5 mg on demand over the first 90 minutes. Further doses up to atotal of 400 mg tramadol or 40 mg morphine could then be given after 90minutes up to 24 hours after the first dose of study medication. Theprimary efficacy parameter was the responder rate (no or slight pain)within the first 90 minutes of treatment. Responder rates were 72.6% fortramadol and 81.2% for morphine, which were statistically equivalent andwithin the predefined range of ±10%. Mean cumulative doses were 188.2 mgfor the first 90 minutes and 157.1 mg for the subsequent 22.5 hours inthe tramadol group and 13.9 mg and 18.4 mg, respectively in the morphinegroup. The main adverse events were gastrointestinal in both groups,with mild nausea, dry mouth, vomiting, dyspepsia and hiccups reportedmost frequently.

The analgesic effect of continuous infusion of tramadol was compared torepeated bolus administration in 135 patients undergoing abdominalsurgery (Rud U, Fischer M V, Mewes R, Paravcini D., “PostoperativeAnalgesie mit Tramadol Kontinuierliche Infusion versus repetitive”(Postoperative analgesia with tramadol. Continuous infusion versusrepetitive bolus administration), Bolusgabe Anaesthesist. 1994;43:316-321. (German)). Patients were randomized at the time of the firstrequest for pain treatment. All patients received a loading dose oftramadol 100 mg i.v. Subsequent treatment was administered in adouble-blind manner; patients in the infusion group were given acontinuous infusion of tramadol 12 mg/h for 24 hours, whereas patientsin the bolus group received placebo infusion. In both groups, additionalbolus doses of tramadol 50 mg i.v. were given as required. Pain reliefwas monitored by means of a visual analog scale (VAS) up to 6 hoursafter surgery. The number of additional boluses and the amount oftramadol administered at 6 hours and 24 hours was also used to assessanalgesic efficacy. More patients in the infusion group assessed theirpain relief as excellent or good compared to the bolus group (76.5% vs65.6%). Only a few patients complained of insufficient analgesia, withmore patients in the bolus group reporting inadequate pain relief thanin the infusion group (7.5% vs 4.4%). A higher percentage of patients inthe bolus group required two or more boluses compared to the infusiongroup (59.7% vs 30.8%). After 6 hours, the average tramadol consumptionwas 223.5±53.7 mg in the infusion group and 176.6±63.1 mg in the bolusgroup (p≤0.05). After 24 hours, tramadol consumption was 449.5±66.0 mgand 201.6±83.9 mg (p≤0.001), respectively. Adverse events were reportedby 25% of patients in both groups, with no significant differences andno patient terminated the trial for an adverse event. There were nosignificant effects on blood pressure or heart rate. The authorsconcluded that continuous infusion was more effective in the first 6hours after surgery. However, excess consumption by the infusion groupwas statistically greater than the bolus group at both 6 hours and 24hours post-surgery.

Intermittent bolus and continuous infusion of tramadol were evaluated ina postoperative study of 35 patients undergoing major abdominalgynecologic surgery (Chrubasik J, Buzina M, Schulte-Monting J,Atanassoff P, Alon E. Intravenous tramadol for post-operativepain-comparison of intermittent dose regimens with and withoutmaintenance infusion. Eur J Anaesthesiol. 1992; 9:23-28). The study wasrandomized and double-blind and used tramadol infusion 15 mg/h orsaline. Additional boluses of tramadol 100 mg were given as requested.The patients in the infusion group required 60% less tramadol on demand(p<0.01) and had better pain relief (p<0.05), as assessed by VAS, thanthe group that received the saline infusion. Total tramadol consumption,however, was about 30% higher in the infusion group (p<0.05) and wasassociated with and increased incidence of minor adverse events.Tramadol was ineffective as pain relief within 2 hours of the beginningof treatment in 6% of the infusion group and 20% of the bolus group.Thus, continuous infusion was preferred to “on-demand” bolus treatment.

A meta-analysis of nine randomized, controlled trials indicated thattramadol was as effective as other opioids, including morphine, forcontrol of postoperative pain (Scott and Perry, 2000). Pain in thesepatients was described as moderate to severe, with initial postoperativepain reported as >60 on a 100-point visual analog scale or as moderateor severe on a 4- or 5-point verbal response scale. The first dose ofanalgesia was administered when patients reported moderate to severepain in the postoperative setting. Studies that did not adequatelyrecord baseline pain severity or response to analgesia, were notrandomized or controlled or contained less than 45 patients wereexcluded from the meta-analysis. Tramadol, administered in a dosetitrated to pain response and via either IV (intravenous) or IM(intramuscular) intermittent injection, reduced pain intensity by 46.8%to 57.6% after 4 to 6 hours compared to 69.8% for morphine and 25.6% to51.3% for pentazocine. Efficacy of tramadol was maintained for theduration of the studies, which were ≤72 hours, and was comparable tomorphine or alfentanil. However, the onset of action of tramadol wasslower than morphine, as assessed by measurements approximately 3 hoursafter the first dose. There were no significant differences in thepercentage of patients treated with tramadol or morphine and who alsorequired rescue medication. The patient global response and physicianglobal response were similar for tramadol and for other opioids.

Tramadol injection (IV/IM/SC) is approved and used for the management ofmoderate to severe acute postoperative pain in several regions,including Europe, India and Australia/New Zealand (however, this dosageform is not available in the USA). Tramadol ampoules or vials for IV, IMand SC administration and preservative-free solutions for injection bythe various spinal routes (epidural, intrathecal, caudal, etc.) areavailable forms in these regions. Tramadol formulations approved inseveral countries include, tablets, capsules, effervescent powders, andsuppositories (Grond and Sablotzki, 2004; Rosenberg, 2009).

There is extensive data demonstrating that tramadol use is notassociated with the classical opioid side effects seen with more potentopioids. There are numerous reports of the safety and efficacy oftramadol (Lee et al., 1993; Scott and Perry, 2000; Grond and Sablotzki,2004). The most common adverse events of tramadol administration arenausea, dizziness, headache, somnolence, sweating, fatigue,constipation, dry mouth and vomiting. However, tramadol use,particularly with high doses, has been associated with seizures, and therisk of seizures is increased in the presence of drugs that reduceseizure threshold, head trauma or prior history of seizures.

Patients undergoing surgery, for example, total knee arthroplasty (TKA)and total hip arthroplasty (THA), typically demonstrate a need forshort-term analgesia, which is critical for earlier mobilization andrehabilitation. In this setting, assuring adequate pain relief withoutproviding extensive medical oversight required for some methods oftreatment (such as neuraxial anesthesia) and prevention of effects suchas opiate-induced respiratory depression and dependency would be highlybeneficial (Sinatra et al., 2002).

The goal of post-surgical pain management is twofold: i) to provide aquick onset of analgesic or pain relief and ii) to reduce or modulatethe quality and intensity of pain that a patient experiences in thepost-surgical period. While current treatments for management ofpost-surgical acute pain are useful, there is a need for improvedmethods for treating post-surgical acute pain.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method of treatingpain in human patients.

It is a further object of the present invention to provide a method oftreating pain in human patients who are unable to take oral medications,such as in a post-operative condition.

It is a further object of the present invention to provide a method oftreating pain in human patients that takes advantage of the faster onsetof intravenous administration of tramadol while providing additionalbenefits not available via current methodologies of tramadol intravenousadministration.

It is another object of the present invention to provide a method ofproviding a safe and effective alternative injectable analgesic for usein the acute postoperative setting.

It is another object of the present invention to provide a method fortreating pain in, e.g., the acute postoperative setting which is or maybe opioid-sparing.

It is another object of the present invention to provide a method fortreating pain with intravenous tramadol in human patients in a mannerthat may or does reduce side-effects (such as, e.g., nausea, vomiting orseizure).

It is a further object of the present invention to provide a method oftreating pain with a drug and dosing regimen that provides a positivebenefit-risk profile, and which addresses an unmet medical need for themanagement of acute postoperative pain.

It is an object of the present invention to provide an intravenousdosing regimen for tramadol using a lower dose than that previouslyconsidered to be useful by those skilled in the art.

It is an object of the present invention to provide a dosing regimen forintravenous tramadol that provides treating physicians with a clearpicture of what tramadol blood plasma levels they are obtaining inrelation to oral tramadol (a drug that they are very familiar with).

In accordance with the above objects and others, the present inventionis directed in part to a method of administering tramadol for treatingpain via an intravenous dosing regimen comprising or consisting ofintravenously administering a first dose of tramadol to a human patientin an amount of about 25 to less than 50 mg; intravenously administeringa second dose of tramadol to the human patient in an amount from about25 mg to about 50 mg at about 2 hours after the first dose;intravenously administering a third dose of tramadol to the humanpatient in an amount from about 25 mg to less than 50 mg at about 2hours after the second dose; and thereafter intravenously administeringfrom about 25 mg to less than 50 mg tramadol at dosage intervals ofabout 4 hours, until the patient no longer requires treatment withtramadol. In certain preferred embodiments, the intravenous dosingregimen provides a Cmax and AUC of tramadol which is similar to the Cmaxand AUC of an oral dose of 50 mg tramadol HCl given every 6 hours atsteady-state.

In certain preferred embodiments, the Cmax of the intravenous dose of 25mg at 4 hours after administration of the first intravenous dose (i.e.,after the third intravenous dose) is similar to the steady-state Cmaxachieved with an oral tramadol dose of 50 mg administered every 6 hours(the Cmax of the oral tramadol dosing regimen not occurring until about44 hours after the first dose). In certain preferred embodiments, thedose administered each time is about 25 mg. In certain preferredembodiments, the method comprises administering from about 175 mg toabout 343 mg tramadol intravenously over an initial 24 hour period oftreatment, and a daily dose from about 150 mg to about 294 mg dailythereafter.

The present invention is further directed in part to a method ofadministering tramadol for treating pain via an intravenous dosingregimen comprising or consisting of intravenously administering a firstdose of tramadol to a human patient in an amount of about 25 mg;intravenously administering a second dose of tramadol to the humanpatient in an amount of about 25 mg at about 2 hours after the firstdose; intravenously administering a third dose of tramadol to the humanpatient in an amount of about 25 mg at about 2 hours after the seconddose; and thereafter intravenously administering about 25 mg tramadol atdosage intervals of about 4 hours, until the patient no longer requirestreatment with tramadol. In certain preferred embodiments, theintravenous dosing regimen provides a Cmax and AUC of tramadol which issimilar to the Cmax and AUC of an oral dose of 50 mg tramadol HCl givenevery 6 hours at steady-state. In certain preferred embodiments, themethod comprises administering from about 200 mg tramadol intravenouslyover an initial 24 hour period of treatment, and a daily dose from about175 mg daily thereafter.

The present invention is further directed in part to a method ofadministering tramadol for treating pain via an intravenous dosingregimen comprising or consisting of intravenously administering a firstdose of tramadol to a human patient in an amount from about 25 mg toless than 50 mg; intravenously administering a second dose of tramadolto the human patient in an amount of about 50 mg or from about 25 mg toless than 50 mg at about 2 hours after the first dose; intravenouslyadministering a third dose of tramadol to the human patient in an amountfrom about 25 mg to less than 50 mg (and in certain embodimentspreferably about 25 mg) at about 2 hours after the second dose; andthereafter intravenously administering from about 25 mg to less than 50mg tramadol (and in certain embodiments preferably about 25 mg) atdosage intervals of about 4 hours, until the patient no longer requirestreatment with tramadol. In certain preferred embodiments, theintravenous dosing regimen provides a Cmax and AUC of tramadol which issimilar to the Cmax and AUC of an oral dose of 50 mg tramadol HCl givenevery 6 hours at steady-state.

In other embodiments, the present invention is directed in part to amethod of administering tramadol for treating pain via an intravenousdosing regimen comprising or consisting of intravenously administering afirst dose of tramadol to a human patient in an amount of about 25 mg;intravenously administering a second dose of tramadol to the humanpatient in an amount from about 25 mg to about 50 mg (or any tramadoldose in between those doses) at about 2 hours after the first dose;intravenously administering a third dose of tramadol to the humanpatient in an amount from about 25 mg to less than 50 mg (or anytramadol dose in between those doses) at about 2 hours after the seconddose; and thereafter intravenously administering from about 25 mg toabout 50 mg (or any tramadol dose in between those doses) tramadol atdosage intervals of about 4 hours, until the patient no longer requirestreatment with tramadol. In certain preferred embodiments, the doseadministered each time is about 25 mg. Preferably, the mean tramadolconcentration for the intravenous dosing regimen provides similarsteady-state peak and trough concentrations as compared to a dosingregimen of 50 mg tramadol HCl administered orally every 6 hours atsteady-state. In certain preferred embodiments, the method comprisesadministering from about 175 mg to about 343 mg tramadol intravenouslyover an initial 24 hour period of treatment, and a daily dose from about150 mg to about 294 mg daily thereafter.

In a preferred embodiment, the dosing regimen comprises or consists of25 mg IV tramadol at hour 0, followed by 25 mg at hour 2, 25 mg at hour4, and 25 mg every 4 hours thereafter (e.g., until the patient no longerrequires treatment with intravenous tramadol, e.g. about 48 hours afterthe first dose (with the last intravenous dose being administered 44hours after the first dose)).

The invention is further directed in part to a method of administeringtramadol for treating pain in a human patient(s) via an intravenousdosing regimen, comprising intravenously administering a first dose oftramadol to a human patient(s) in an amount of about 25 mg;intravenously administering a second dose of tramadol to the humanpatient(s) in an amount of about 25 mg at about 2 hours after the firstdose; intravenously administering a third dose of tramadol to the humanpatient(s) in an amount of about 25 mg at about 2 hours after the seconddose; and thereafter intravenously administering additional doses oftramadol to the human patient(s) in an amount of about 25 mg tramadol atdosage intervals of about 4 hours, such that the mean Cmax concentrationafter administration of the third administered dose of tramadol issimilar to the mean Cmax of the intravenous dosing regimen atsteady-state and is similar to the Cmax at steady-state for a dosingregimen of 50 mg tramadol HCl administered orally every 6 hours, whereinthe tramadol is tramadol base or a pharmaceutically acceptable salt oftramadol.

The invention is further directed in part to a method of administeringtramadol for treating pain in a human patient(s) via an intravenousdosing regimen, comprising intravenously administering a first dose oftramadol to a human patient(s) in an amount of about 25 mg;intravenously administering a second dose of tramadol to the humanpatient(s) in an amount of about 25 mg at about 2 hours after the firstdose; intravenously administering a third dose of tramadol to the humanpatient(s) in an amount of about 25 mg at about 2 hours after the seconddose; and thereafter intravenously administering additional doses oftramadol to the human patient(s) in an amount of about 25 mg tramadol atdosage intervals of about 4 hours, such that the intravenous dosingregimen provides a Cmax of tramadol at steady-state from about 80% toabout 125% of about 368 ng/mL (i.e., from about 294 ng/ml to about 460ng/ml). Preferably, the Cmin of tramadol at steady-state via thisintravenous dosing regimen is about 224±66 ng/ml, or from about 80% toabout 125% of about 224 ng/ml (i.e., from about 179 to about 280 ng/ml).

The invention is further directed in part to a method of administeringtramadol for treating pain in a human patient(s) via an intravenousdosing regimen, comprising intravenously administering a first dose oftramadol to a human patient(s) in an amount of about 25 mg;intravenously administering a second dose of tramadol to the humanpatient(s) in an amount of about 25 mg at about 2 hours after the firstdose; intravenously administering a third dose of tramadol to the humanpatient(s) in an amount of about 25 mg at about 2 hours after the seconddose; and thereafter intravenously administering additional doses oftramadol to the human patient(s) in an amount of about 25 mg tramadol atdosage intervals of about 4 hours, such that the peak/trough ratio oftramadol at about 44 hours after the first administered dose of tramadolis about 1.637±0.2655.

The invention is further directed in part to a method of administeringtramadol for treating pain in a human patient(s) via an intravenousdosing regimen, comprising intravenously administering a first dose oftramadol to a human patient(s) in an amount of about 25 mg;intravenously administering a second dose of tramadol to the humanpatient(s) in an amount of about 25 mg at about 2 hours after the firstdose; intravenously administering a third dose of tramadol to the humanpatient(s) in an amount of about 25 mg at about 2 hours after the seconddose; and thereafter intravenously administering additional doses oftramadol to the human patient(s) in an amount of about 25 mg tramadol atdosage intervals of about 4 hours, such that the Cmax after the seconddose is approximately 50% higher than Cmax after the first dose, andthat the Cmax after the 3rd dose is approximately 50% higher than theCmax after the second dose, and that the Cmax after further doses arecomparable to Cmax after the 3rd dose. In certain preferred embodiments,the intravenous dosing regimen provides a Cmax and AUC of tramadol whichis similar to the Cmax and AUC of an oral dose of 50 mg tramadol HClgiven every 6 hours at steady-state.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide a Cmax of tramadol at steady-state that is similar orsubstantially the same as the Cmax provided at steady-state by a 50 mgoral dose of tramadol HCl given every 6 hours.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide a Cmax of tramadol at steady-state that is from about80% to about 125% of the Cmax provided at steady-state by a 50 mg oraldose of tramadol HCl given every 6 hours.

In certain preferred embodiments, the intravenous dosing regimens of thepresent invention provide an AUC of tramadol at steady-state that isfrom about 80% to about 125% of the AUC provided at steady-state by a 50mg oral dose of tramadol HCl given every 6 hours.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide a Cmax of the M1 metabolite of tramadol atsteady-state that is from about 20% to about 100% (in certainembodiments from about 60% to about 75%), or from about 80% to about100% of the Cmax of the M1 metabolite of tramadol at steady-state whenthe tramadol is administered as oral 50 mg tramadol HCl every 6 hours.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide an AUC of the M1 metabolite of tramadol atsteady-state which is from about from about 20% to about 100% (incertain embodiments from about 60% to about 75%), or from about 80% toabout 100% of the steady-state AUC of the M1 metabolite of tramadol whenthe tramadol is administered as oral 50 mg tramadol HCl every 6 hours.

In certain embodiments of the intravenous dosing regimens of theinvention, the intravenous dosing regimen provides a Cmax of tramadol atsteady-state from about 80% to about 125% of about 368 ng/mL.

In certain embodiments of the intravenous dosing regimens of theinvention, the intravenous dosing regimen provides a Cmax of the M1metabolite of tramadol at steady-state which is 48.3 ng/ml±12.3, orwhich is from about 80% to about 125% of about 48.3 ng/mL (i.e., fromabout 80 ng/ml to about 125 ng/ml). In certain embodiments of theintravenous dosing regimens of the invention, the intravenous dosingregimen provides an AUC₀₋₂₄ of the M1 metabolite of tramadol which isabout 1001 ng·h/ml±257.5, or from about 80% to about 125% of about 1001ng·h/ml.

In preferred embodiments of the intravenous dosing regimens of theinvention, each dose of tramadol is administered intravenously over atime period from about 10 minutes to about 20 minutes. In certainpreferred embodiments, each dose of the tramadol is administered over atime interval of 15 (±2) minutes.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering a first doseof tramadol to the patient intra-operatively at wound closure, or fromfirst demand of analgesia post-operatively, and administering saidfurther doses of intravenous tramadol for at least two dayspost-surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering one or moredoses of an intravenous opioid analgesic as rescue medicine to thepatient to treat breakthrough pain.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering the first doseof tramadol on first demand of analgesia post-operatively, furthercomprising administering a therapeutically effective dose intravenousopioid analgesic to the patient at the end of the surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering the first doseof tramadol to the patient intra-operatively at wound closure, furthercomprising administering a bolus of a therapeutically effective dose ofintravenous opioid analgesic to the patient if the patient requestsanalgesia before the second dose of tramadol.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering a rescueopioid analgesic using Patient Controlled Analgesia (PCA).

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the treatment of pain in the patient is opioid-sparingover the first 48 hours post-surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises diluting tramadol in avolume of normal saline to provide a unit dose (e.g., of about 25 mgtramadol) in said volume of normal saline; administering the dose oftramadol intravenously over a time period from about 10 to about 20minutes, preferably about 15 (±2) minutes.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the dose prior to dilution is contained in one or moreampoules.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the ampoules contain tramadol hydrochloride and abuffering agent in water for injection.

In certain embodiments of the intravenous dosing regimens of theinvention, the human patient(s) is suffering from acute post-operativepain.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method provides a reduction in at least oneside-effect associated with tramadol therapy (e.g., as compared to priorart intravenous dosing regimens), wherein the side-effect is nausea,vomiting, or seizure.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering atherapeutically effective dose of an intravenous opioid analgesic isadministered to the patient (i) at the end of the surgery, (ii) if thepatient requests analgesia before the second dose of tramadol, or (iii)both (i) and (ii).

In certain preferred embodiments, the present invention is directed inpart to a method of treating pain, comprising administering to a humanpatient(s) a therapeutically effective dose of tramadol intravenouslyover a time period from about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20 21, 22, 23, 24, 25, 26, 27, 28, 29 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44 or 45 minutes.

Further aspects of the invention are directed to diluting the dose oftramadol in from about 50 ml to about 500 ml (and preferably from about50 ml to about 100 ml) of a pharmaceutically acceptable fluid forinjection such as normal saline, e.g., in a bag, and standardizing theadministration of the injection of the dose of tramadol via the use of apump.

In another preferred embodiment, the dose of tramadol is provided in theform of a sterile solution at a concentration of about 12.5 mg to about25 mg, or up to about 50 mg or 100 mg tramadol hydrochloride/1 ml priorto dilution.

In certain further preferred embodiments, the dose of tramadol prior todilution is contained in one or more ampoules. In certain preferredembodiments, the ampoules contain the dose of tramadol (e.g., tramadolhydrochloride) together with a buffering agent (e.g., sodium acetate) inwater for injection (e.g., about 1 ml to about 5 ml).

In certain further preferred embodiments, the method further comprisesdiluting the dose of tramadol into an IV bag for administration to thepatient.

In certain preferred embodiments of the present invention, the methodfurther comprises administering a first dose of tramadol to the patientintra-operatively at wound closure, or from first demand of analgesiapostoperatively, and administering said further doses of intravenoustramadol for at least two days post-surgery.

In certain preferred embodiments of the present invention, the methodfurther comprises the concomitant administration of one or more opioidanalgesics, preferably via the injectable (e.g., intravenous) route asrescue medicine to the patient to treat breakthrough pain that thepatient experiences, e.g., for the time period of at least about 48hours post-surgery. Several options are available for postoperative painmanagement (Singelyn et al., 1998; Sinatra et al., 2002; both of whichare hereby incorporated by reference). Options include intermittent“on-demand” analgesia, continuous epidural analgesia with opioids and/orlocal anesthetics is effective, or to provide a combination of nerveblocks with long-acting local anesthetics and/or opioids initiatedintra-operatively and continued into the immediate postoperative period.For example, most Total knee Arthroplasty (TKA) or Total HipArthroplasty (THA) procedures are currently performed with regional (orneuraxial) or other nerve blocks and without general anesthesia. Incertain preferred embodiments of the invention, the method furthercomprises administering a rescue opioid analgesic using PatientControlled Analgesia (PCA). In certain preferred embodiments, theintravenous administration of opioid analgesic also or alternativelycomprises opioid analgesic (e.g., morphine) intravenously to the patientat an effective dose (e.g., morphine in an amount of about 0.05 mg/kg)as a bolus at the end of surgery or upon first demand of analgesiapostoperatively, to provide effective analgesia to the patient(s).

In certain preferred embodiments of the invention, the first dose oftramadol is administered on first demand of analgesia postoperatively.Thereafter, the method may further comprise administering atherapeutically (analgesically) effective dose intravenous opioidanalgesic to the patient at the end of the surgery, to provide effectiveanalgesia to the patient(s).

In certain preferred embodiments of the invention, the first dose oftramadol is administered to the patient intra-operatively at woundclosure. In such embodiments, the method may further compriseadministering a bolus of a therapeutically (analgesically) effectivedose of intravenous opioid analgesic to the patient if the patientrequests analgesia before the second dose of tramadol, to provideeffective analgesia to the patient(s).

In preferred embodiments where the tramadol is administered for thetreatment of post-operative pain, the treatment of pain in the patientis opioid-sparing over the first 48 hours post-surgery.

In other preferred embodiments, the human patient(s) suffering from painis unable to ingest an oral dosage form (e.g., of tramadol or anotheropioid analgesic and/or an NSAID) because the patient is suffering fromcancer pain.

In accordance with the above, the final drug product (containing theintravenous dose of tramadol) may be presented as, e.g., as unit-doseampoules, unit-dose vials, multi-dose ampoules, multi-dose vials, anddrug in pre-mixed bags.

In certain preferred embodiments, the M1 metabolite of tramadol(O-desmethyltramadol) contributes to analgesic effect provided by thepresent invention (dosing regimen), without being toxic (e.g., withoutsignificant side effects) to humans at the administered dose ofintravenous tramadol.

The invention is further directed in part to a method of improving thesafety and tolerability of tramadol for treating pain in human patients,comprising intravenously administering intravenously administering about25 mg tramadol at a dosage interval of about 4 hours, except for anadditional loading dose administered about 2 hours after the firstintravenous dose of tramadol, such that the intravenous dosing regimenprovides a steady-state Cmax and AUC of tramadol at about 4 to about 12hours after initiation of intravenous tramadol therapy, which is similarto the steady-state Cmax and AUC of oral doses of 50 mg tramadol HClgiven every 6 hours.

In certain preferred embodiments, the present methods are used to treathuman patient(s) suffering from acute post-operative pain. In furtherembodiments, the method may result in a reduction in at least oneside-effect associated with tramadol therapy, wherein the side-effect isnausea, vomiting, or seizure. In certain preferred embodiments, atherapeutically effective dose of an intravenous opioid analgesic isadministered to the patient (i) at the end of the surgery, (ii) if thepatient requests analgesia before the second dose of tramadol, or (iii)both (i) and (ii). In certain preferred embodiments, each dose oftramadol is administered intravenously over a time period from about 10minutes to about 20 minutes, or each dose of tramadol is administeredover a time interval of 15 (±2) minutes. In certain preferredembodiments, the pharmacokinetic profile (e.g., plasma concentrationcurve of tramadol and/or the M1 metabolite of tramadol) achieved withthe (e.g., about) 25 mg dosing regimen provides surprisingly reducedfluctuation (e.g., peak to trough variance) as compared to a higher(e.g., 75 mg or 100 mg) intravenous dosing regimen. In certain preferredembodiments, the pharmacokinetic profile (e.g., Cmax and AUC) achievedby this IV tramadol dosing regimen at a time where the patient might beswitched to oral meds (e.g., after the 44-48 hour dosing interval) issimilar to the pharmacokinetic profile (e.g., Cmax and AUC) provided atsteady-state by a dosing regimen of 50 mg tramadol HCl administeredorally every 6 hours. This allows the patient to be stepped down fromthe intravenous tramadol dosing regimen to an oral dosing regimen. Inturn, this allows the patient to be discharged from hospital care withless concern about deleterious effects which might occur from a switchfrom intravenous to oral analgesic medicine (e.g., the switch to an oralversion of the drug providing a much different Cmax and AUC).

The methods of the present invention are described in further detail inthe following sections. However, it should be understood that forpurposes of the present invention, the following terms have thefollowing meanings:

For purposes of the present invention, the phrase “from about 25 mg toless than 50 mg” means that the dose of intravenous tramadol may be,e.g., 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49mg, and 49.5 mg.

With respect to the second dose of intravenous tramadol administered tothe human patient in this method, for purposes of the present inventionthe term “about 50 mg” means, e.g., from about 45 mg to about 55 mg, or45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg,and 55 mg.

For purposes of the present invention, the term “less than 50 mg” means,e.g., that the dose of intravenous tramadol may be 1 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45mg, 46 mg, 47 mg, 48 mg, 49 mg, and 49.5 mg.

The term “acute pain” as used herein means pain that has a sudden onsetand commonly declines over a short time (days, hours, minutes) andfollows injury to the body and which generally disappears when thebodily injury heals.

The term “effective analgesia” is defined for purposes of the presentinvention as a satisfactory reduction in or elimination of pain, alongwith the process of a tolerable level of side effects, as determined bythe human patient.

The term “effective pain management” means for purposes of the presentinvention as the objective evaluation of a human patient's response(pain expressed versus side effects) to analgesic treatment by aphysician as well as subjective evaluation of therapeutic treatment bythe patient undergoing such treatment. The skilled artisan willunderstand that effective analgesia will vary according to many factors,including individual patient variations.

The term “breakthrough pain” means pain which the patient experiencesdespite the fact that the patient is being administered generallyeffective amounts of, e.g., an opioid analgesic such as buprenorphine.

The term “rescue” refers to a dose of an analgesic which is administeredto a patient experiencing breakthrough pain.

An “effective amount” is an amount sufficient to effect beneficial ordesired clinical results including alleviation or reduction in pain. Insome embodiments, the “effective amount” may reduce the pain of ongoingpain and/or breakthrough pain (including ambulatory pain andtouch-evoked pain).

The term “parenterally” as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques.

The term “patient” as used herein refers to a warm blooded animal suchas a mammal which is the subject of trauma, e.g., surgical trauma. It isunderstood that at least humans, dogs, cats, and mice are within thescope of the meaning of the term.

As used herein, the term “treat” or “treatment”, or a derivativethereof, contemplates partial or complete inhibition of acute pain, whena composition of the present invention is administered following theonset of acute pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing a mean plasma concentration-time profile(linear scale) for intravenous tramadol administered at a dose of 25 mgas per Example 2;

FIG. 2 provides a mean plasma concentration-time profile (log scale) forintravenous tramadol administered at a dose of 25 mg as per Example 2;

FIG. 3 provides a mean plasma concentration-time profile (linear scale)for O-Desmethyltramadol when intravenous tramadol is administered at adose of 25 mg as per Example 2; and

FIG. 4 provides a mean plasma concentration-time profile (log scale) forO-Desmethyltramadol when intravenous tramadol is administered at a doseof 25 mg as per Example 2.

DETAILED DESCRIPTION

The chemical name for tramadol is(±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride [or(1R,2R)-rel-2-[(dimethyl-amino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride, (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride,(±)-(RR,SS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride]. Unless otherwise specified, the term tramadol refers tothe racemic mixture of the (±)cis isomers.

Tramadol is a centrally-acting synthetic analgesic of theaminocyclohexanol group with opioid-like effects. Tramadol isextensively metabolized following administration resulting in a numberof enantiomeric metabolites which display different opioid-receptorbinding properties, and monoaminergic reuptake inhibition (Grond andSablotzki, 2004). Both enantiomers of tramadol and (+)-M1 areresponsible for the analgesic effect. The primary metabolite [(+)-M1 or(+)-O-desmethyltramadol] of tramadol confers significant μ-opioidactivity; (+)-tramadol confers weak μ-opioid activity and significantserotonin reuptake inhibition; and (−)-tramadol is responsible for theinhibition of noradrenaline re-uptake (Gillen et al., 2000; Raffa,2008). Nonclinical studies have shown that antinociception induced bytramadol is only partially antagonized by the opiate antagonist,naloxone, indicating that non-opioid mechanisms are also involved in itspharmacodynamic action (Collart et al., 1992).

Tramadol has efficacy in management of acute postoperative painequivalent to morphine and other opioids administered intravenously,although the onset of action for tramadol is slower. The parenteralroute has the advantage of immediate bioavailability and faster onset ofaction than oral, and is available to postoperative patients who cannottake oral medications. Current standard-of-care injectable analgesics(opioids and NSAIDs) have significant adverse effects, includingopiate-induced respiratory depression, excessive sedation, hypotension,dependency, increased bleeding risk, renal toxicity and gastrointestinalirritation, which can potentially slow the postoperative rehabilitationprocess and compound the risk inherent in any surgical procedure.

Tramadol is currently commercially available in variouscountries/territories in the following forms: 50 mg/ml or 100 mg/2 ml,solution for injection; 50 mg, capsules, hard; 50 mg, prolonged-releasetablets; 100 mg, prolonged-release tablets; 150 mg, prolonged-releasetablets; 200 mg, prolonged-release tablets; 50 mg, tablets; 100 mg/ml,oral drops, solution; and 100 mg, suppositories. In the U.S., tramadolis approved by the Food and Drug Administration (FDA) and marketed as anoral capsule/tablet for moderate to moderately severe pain in adults,e.g., under the tradename Ultram® (tramadol hydrochloride tablets).

Parenteral tramadol has been used extensively in Europe and other areasof the world for the amelioration of postoperative pain in both adultsand children. The efficacy of tramadol has been thoroughly reviewed (LeeC R, McTavish D, Sorkin E M. Tramadol. A preliminary review of itspharmacodynamic and pharmacokinetic properties, and therapeuticpotential in acute and chronic pain states. Drugs. 1993; 46:313-340;Scott L J, Perry C M. Tramadol. A review of its use in perioperativepain. Drugs. 2000; 60:139-176; Grond S and Slabotzi A. Clinicalpharmacology of tramadol. Clin Pharmacokinet. 2004; 43:879-923).Parenteral tramadol in such territories consists of tramadol 50 mg or100 mg administered as a slow bolus injection (over 2-3 minutes) every4-6 hours. Despite the availability of parenteral (e.g., intravenous)and oral forms of tramadol, Applicant is not aware of any establisheddosing regimen of parenteral (e.g., intravenous) tramadol in a dose ofless than 50 mg, e.g., 25 mg for adult human patients. However, at page6 of the product label for Ultram® in the U.S., it is reported that a16-day titration schedule, starting with 25 mg qAM and using additionaldoses in 25 mg increments every third day to 100 mg/day (25 mg fourtimes per day), followed by 50 mg increments in the total daily doseevery third day to 200 mg/day (50 mg four times per day), resulted infewer discontinuations due to nausea or vomiting and fewerdiscontinuations due to any cause than did a 10-day titration schedule.However, this dosage regimen is for chronic pain with oral tramadol.

The product label for Ultram® further states that for patients withmoderate to moderately severe chronic pain not requiring rapid onset ofanalgesic effect, the tolerability of ULTRAM® can be improved byinitiating therapy with the following titration regimen: ULTRAM® shouldbe started at 25 mg/day qAM and titrated in 25 mg increments as separatedoses every 3 days to reach 100 mg/day (25 mg q.i.d.). Thereafter thetotal daily dose may be increased by 50 mg as tolerated every 3 days toreach 200 mg/day (50 mg q.i.d.). After titration, ULTRAM® 50 to 100 mgcan be administered as needed for pain relief every 4 to 6 hours not toexceed 400 mg/day. (page 20-21 of the package insert for ULTRAM®).

Surgical procedures often result in some form of acute pain. Surgicalpain may include nociceptive, neuropathic or psychological components.Nociceptive pain is a pain experienced as a result of nociception, whichis detection of a stimulus by a pain receptor (nociceptor) andtransmission of the information to the brain along nerves. Nociceptivepain is caused by tissue damage and inflammation in response to trauma.The resulting pain is usually not well localized and is opioidresponsive.

Several options are available for postoperative pain management(Singelyn et al., 1998; Sinatra et al., 2002). Options includeintermittent “on-demand” analgesia, continuous epidural analgesia withopioids and/or local anesthetics is effective, or to provide acombination of nerve blocks with long-acting local anesthetics and/oropioids initiated intra-operatively and continued into the immediatepostoperative period. In the United States (US) and in India, thislatter strategy is frequently employed, and most TKA and THA proceduresare currently performed with regional (or neuraxial) or other nerveblocks and without general anesthesia. Each of these options forpostoperative pain management can be used concomitantly with theintravenous tramadol treatments described herein as rescue medicine totreat breakthrough pain.

The present invention is directed in part to tramadol in apharmaceutically acceptable sterile solution formulation containing aneffective dose of tramadol or a pharmaceutically acceptable saltthereof, and a method of administration of the same for the treatment ofpain, e.g., postoperatively. Tramadol injection in accordance with thepresent invention will fulfill an important need by providing a safe andeffective alternative injectable analgesic for use in the acutepostoperative setting.

Preferably, the dose of tramadol administered in accordance with thepresent invention is, e.g., about 25 mg. In certain preferredembodiments, each tramadol dose administered is in the amount of, e.g.,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg, e.g., providedas tramadol hydrochloride. The tramadol may be provided, e.g., as 25 or50 mg tramadol hydrochloride/1 ml. The injectable tramadol dose isgenerally intended for in-hospital use, although it can be used in othersettings. In certain preferred embodiments, the therapeuticallyeffective dose of tramadol intravenously over a time period from about10 minutes to about 20 minutes, and most preferably in certainembodiments about 15 (±2) minutes. Thus, in preferred embodiments, thetherapeutically effective dose of tramadol intravenously over a timeperiod from about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20minutes.

Further aspects of the invention are directed to diluting the dose oftramadol in from about 50 ml to about 100 ml of a pharmaceuticallyacceptable fluid for injection (such as normal saline), andstandardizing the administration of the injection of the dose oftramadol via the use of a pump. In preferred embodiments, the pump is aninfusion pump that is commercially available, such as pumps availablefrom Braun and Hospira.

As previously mentioned, the dose of tramadol administered in accordancewith the present invention may be diluted in a suitable pharmaceuticallyacceptable carrier for injection. Examples of such include sterile waterfor injection, normal saline, etc. Intravenous fluids are well known tothose of ordinary skill in the art, and may include other ingredientsbeyond the dose of tramadol and the carrier/solvent for the tramadol,e.g., sterile solutions of simple chemicals such as sugars, amino acidsor electrolytes, which can be easily carried by the circulatory systemand assimilated. Such fluids are typically prepared with water forinjection USP. Fluids used commonly for intravenous (IV) use aredisclosed in Remington, The Science and Practice of Pharmacy [fullcitation previously provided], and include: alcohol, e.g., 5% alcohol(e.g., in dextrose and water (“D/W”) or D/W in normal saline solution(“NSS”), including in 5% dextrose and water (“D5/W”), or D5/W in NSS);synthetic amino acid such as Aminosyn, FreAmine, Travasol, e.g., 3.5 or7; 8.5; 3.5, 5.5 or 8.5% respectively; ammonium chloride e.g., 2.14%;dextran 40, in NSS e.g., 10% or in D5/W e.g., 10%; dextran 70, in NSSe.g., 6% or in D5/W e.g., 6%; dextrose (glucose, D5/W) e.g., 2.5-50%;dextrose and sodium chloride e.g., 5-20% dextrose and 0.22-0.9% NaCl;lactated Ringer's (Hartmann's) e.g., NaCl 0.6%, KCl 0.03%, CaCl₂ 0.02%;lactate 0.3%; mannitol e.g., 5%, optionally in combination with dextrosee.g., 10% or NaCl e.g., 15 or 20%; multiple electrolyte solutions withvarying combinations of electrolytes, dextrose, fructose, invert sugarRinger's e.g., NaCl 0.86%, KCl 0.03%, CaCl₂ 0.033%; sodium bicarbonatee.g., 5%; sodium chloride e.g., 0.45, 0.9, 3, or 5%; sodium lactatee.g., 1/6 M; and sterile water for injection The pH of such IV fluidsmay vary, and will typically be from about 3.5 to about 8 as known inthe art.

The dose of tramadol or pharmaceutically acceptable salts thereof can beadministered alone or in combination with other medical treatments, orother therapeutic agents, such as NSAIDs. When so-used, othertherapeutic agents can be administered before, concurrently (whether inseparate dosage forms or in a combined dosage form), or afteradministration of an active agent of the present invention.

Consistent with the known clinical effects of opioids, nonclinicalsafety pharmacology studies have shown that tramadol at high dosesaffects the central nervous system (CNS), producing sedation, impairedmobility, vomiting (dogs), decreased activity, and convulsions(Matthiesen et al., 1998). Also consistent with clinical effects,changes in blood pressure have been observed in cardiovascular studiesin rats at high doses (Raimundo et al., 2006). Tramadol use,particularly with high doses, has been associated with seizures, and therisk of seizures is increased in the presence of drugs that reduceseizure threshold, head trauma or prior history of seizures.

The toxicity of tramadol has been summarized by Matthiesen, et al.(1998). The single-dose toxicity of tramadol was similar in all speciestested, independent of the route of administration. Notable acutefindings included restlessness, unsteady gait, reduced spontaneousactivity, exophthalmus, mydriasis, salivation, vomiting (dog), tremor,convulsions, slight cyanosis and dyspnea. The principle findings inrepeat-dose toxicity studies in rats and dogs were behavioral/clinicalsigns and convulsions at doses of ≥25 mg/kg/day. The kidney and liverwere identified as potential target organs in rats, with mild effects(minimal tubular vacuolization and perivenular hydropic degeneration,respectively) following repeat intraperitoneal dosing at high doses oftramadol.

There was no evidence of genotoxic potential for tramadol in standard invitro and in vivo studies (Matthiesen et al., 1998). Carcinogenicitybioassays in mice and rats showed no evidence of carcinogenic potential.An extensive reproductive and teratology program revealed no safetyconcerns with respect to fertility or teratogenic effects after oraladministration (Matthiesen et al., 1998; Yamamoto et al., 1972).Toxicity to offspring only occurred at doses associated with maternaltoxicity.

Following oral administration, tramadol is rapidly and almost completelyabsorbed. The pharmacokinetics of tramadol were evaluated in healthymale volunteers (n=10) in a crossover design using 100 mg PO or IV doses(Lintz et al., 1986). Peak serum concentrations (tmax) were reachedapproximately 2 hours after oral dosing and the peak serum concentration(Cmax) for PO tramadol was 280±49 ng/mL. The terminal half-life was 5.1hours for PO and 5.2 hours for IV administration. The area under theserum tramadol concentration-time curve (AUC) was 2488±774 ng·h/mL forPO and 3709±977 ng·h/mL for IV administration. Total clearance was467±124 mL/min for PO and 710±174 mL/min for IV administration. Theabsolute bioavailability of the oral dose was 68±13%, based oncomparison of the AUC values, while the estimated absorption of the oraldose was 86-88%. The difference between absorption and bioavailabilitywas attributed to first pass metabolism, which was estimated to be ˜20%.However, the absolute bioavailability approaches 90-100% with continuousdosing, probably due to saturation of first pass metabolism (Liao etal., 1992). Other studies have corroborated these findings (Grond andSablotzki, 2004).

The pharmacokinetic profile of tramadol following i.v. and p.o.administration in humans (n=10, male) is summarized in Table A below(Lintz W, Barth H, Osterloh O, Schmidt-Bothelt E. Bioavailability ofenteral tramadol formulations. 1st communication: capsules. ArzneimForsch Drug Res. 1986; 36:1278-1283). The absolute oral bioavailabilityof tramadol was 68% (±13) in humans.

TABLE A Pharmacokinetics of Tramadol (100 mg) Following Intravenous andOral Administration to Humans Tramadol C_(max) AUC_(0-24 h) CL/F (100mg) (ng/mL) t₁/₂ (h) (ng · h/mL) V_(d) (L) (mL/min) i.v. — 5.2 ± 0.83709 ± 977 203 ± 40 467 ± 124 p.o 280 ± 49 5.1 ± 0.8 2488 ± 774 306 ± 52710 ± 174 Abbreviations: C_(max), maximal concentration; t_(1/2),half-life; AUC, area under the plasma concentration-time curve; CL,clearance; F, bioavailability; V_(d), volume of distribution

The pharmacokinetic profile of tramadol and the (+)-M1 and (−)-M1metabolites was also evaluated in humans (N=12, male) following p.o.administration of a single 1.5 mg/kg dose of tramadol (Matthiesen, etal., 1993). The data are summarized in Table B below:

TABLE B Pharmacokinetics of Tramadol and the (+) and (−) Enantiomers ofthe M1 Metabolite Tramadol (1.5 mg/kg, AUC CL/F [100 mg]) C_(max)(ng/mL) T_(max) (h) t₁/₂ (h) (ng · h/mL) (mL/min/kg) Tramadol 274 ± 751.6 ± 0.5 5.9 ± 0.7 2177 ± 722 742 ± 234 (+)-M1 147 ± 39 1.6 ± 0.5 6.0 ±1.0 1258 ± 410 642 ± 204 (−)-M1 125 ± 32 1.5 ± 0.5 5.2 ± 0.8  908 ± 298883 ± 264 Abbreviations: C_(max), maximal concentration; T_(max), timeto maximal concentration; AUC, area under the plasma concentration-timecurve; CL, clearance; F, bioavailability; t₁/₂, half-life; V_(d); volumeof distribution

Tramadol undergoes hepatic metabolism and both the parent drug and theactive metabolite are excreted by the kidneys. The active metabolite, M1(O desmethyltramadol), is produced by the action of CYP2D6 isozyme ofthe cytochrome P450 enzyme system. It has a half-life of approximately6.7 hours after oral administration (single dose of 100 mg), compared toa half-life of 5.6 hours for tramadol administered intravenously.Hepatic impairment results in decreased metabolism of both the parentcompound and the active metabolite. Tramadol is rapidly distributedafter IV administration with a distribution half-life in the initialphase of 0.31±0.17 hours, followed by a slower distribution phase with ahalf-life of 1.7±0.4 hours (Lintz et al., 1986). The volumes ofdistribution following PO and IV administration were 306 L and 203 L,respectively, indicating that tramadol has a high tissue affinity. Theprotein binding of tramadol is approximately 20%; however, saturation ofbinding sites does not occur in the therapeutic dose range (Ultram®Prescribing Information, 2009).

Elimination half-life increases approximately 2-fold in subjects withrenal or hepatic impairment. Patients who metabolize drugs poorly viaCYP2D6 (Caucasian population prevalence ˜8%) may obtain reduced benefitfrom tramadol due to reduced formation of M1 (Ultram® PrescribingInformation, Ortho-McNeil-Janssen Pharmaceuticals, Inc, 2009).

Studies of IV tramadol in the postoperative setting have shown anacceptable safety profile. Loading doses up to 150 mg IV were notassociated with any serious adverse effects (Silvasti et al., 2000).Also, no serious adverse effects were observed in clinical trials oftramadol with mean (±SD) cumulative doses of 449±66 mg (Rud et al.,1994), 677±473 mg (range 128-1750 mg) (Silvasti et al., 2000), and868.3±412.2 mg (Pang et al., 1999) over 24, 36 and 48 h respectively.

The most common adverse events, nausea, dizziness, headache, somnolence,sweating, fatigue, constipation, dry mouth and vomiting, which areusually mild to moderate in severity and only occasionally lead topremature discontinuation of tramadol.

The Ultram® and Tramal® labels contain several warnings and precautionsregarding use of tramadol. The risk of most of these potential adverseevents can be minimized by decreasing the dose or excluding use oftramadol in subjects with risk factors associated with these known, rareadverse events. Tramadol metabolism is reduced in the setting ofadvanced cirrhosis and renal clearance of both tramadol and itsmetabolites is reduced in individuals with creatinine <30 mL/min. Thus,the dose of tramadol should be reduced by half or the interval doubledin these populations. Dosage adjustment is also recommended inindividuals >75 years of age as they have reduced drug clearance.Tramadol is metabolized by CYP2D6 and CYP3A4; thus, drugs that areinhibitors or inducers of these enzymes can alter tramadol metabolism,resulting in decreased efficacy and/or increased risk of seizures orother adverse effects. Tramadol is associated with a low risk forrespiratory depression, which is increased in the presence of otheropioids, anesthetic agents and other CNS depressants, including alcohol.Respiratory depression due to the opioid activity of tramadol can bereversed with naloxone. Naloxone should be used cautiously as it canpotentiate seizures when administered with tramadol. The full range ofallergic/hypersensitivity reactions have been reported in associationwith tramadol administration, including serious and rarely fatalanaphylactoid reactions.

Potentially life-threatening serotonin syndrome may occur with tramadolproducts with concomitant use of serotonergic drugs such as SSRIs,tricyclic antidepressants, monoamine oxidase inhibitors and triptans.

Tramadol use, particularly with high doses, has been associated withseizures, and the risk of seizures is increased in the presence of drugsthat reduce seizure threshold, head trauma or prior history of seizures.

Human studies evaluating the abuse potential of tramadol, administeredvia IV or PO routes, have also been conducted (Epstein et al., 2006).During the initial dose-ranging studies, seizure was observed followinga tramadol dose of 700 mg IV administered over 1 minute and 300 mg IVdelivered over 2.5 minutes. No seizures were observed with a tramadoldose of 200 mg IV administered over 5 minutes. The authors hypothesizedthat toxicity is likely to limit abuse of high doses of IV tramadol. Ina subsequent study involving 10 experienced opioid abusers, tramadol(100 and 200 mg IV), morphine (10 and 20 mg IV) and placebo wereadministered over 5 minutes. The endpoints in the study were subjective;the extent to which subjects “liked” the effects of the drugs, as wellas their ability to produce effects common to morphine and henzadrine(assessed by the Addiction Research Center Inventory-Morphine BenzadrineGroup [ARCI-MBG] scale). Tramadol and morphine significantly increasedratings of “feel drug effect” compared to placebo. However, neither doseof tramadol increased ratings on the “liking” or ARCI-MBG scale or onany other subjective measure of opiate-like effects. In contrast,morphine 10 and 20 mg doses significantly increased ratings of “liking”and the morphine 20 mg dose increased ratings on the ARCI-MBG scale.Thus, tramadol administered via the parenteral route (IV or IM) isunlikely to be associated with the subjective morphine-like and positivemood effects typical of abuse and addiction.

In accordance with the present invention, it is desirable to provide anintravenous dosing regimen of tramadol which at steady-state provides aplasma concentration with respect to Cmax and AUC that is similar orequivalent to the steady-state Cmax and AUC provided by a 100 mg oraltramadol dose given every 6 hours would be desirable and would be saferand have less likelihood of significant side effects than, e.g., theadministration of 50 or 100 mg of tramadol intravenously administeredevery 6 hours (i.e., same dose and dosing interval as the oral referencestandard, Ultram®. It is further believed that it would desirable forsuch an intravenous dosing regimen(s) to provide a steady-state troughplasma level of tramadol (e.g., Cmin) which is at least as high as thesteady-state trough level provided by a 50 mg oral tramadol dose givenevery 6 hours. It is further desirable in accordance with the presentinvention to provide a dosing regimen which reaches but does notsubstantially exceed the maximum (Cmax) and minimum (Cmin) plasma levelsof tramadol obtained at steady-state by a 50 mg oral tramadol dose givenevery 6 hours as soon as possible within the dosing regimen, e.g., priorto the end of the initial 24 hours of intravenous tramadol, or sooner.As will be explained further herein, for purposes of the presentinvention the steady-state Cmax of the 50 mg oral dose of tramadoladministered every 6 hours is about 368 ng/mL. For purposes of thepresent invention, a similar or equivalent Cmax provided by anintravenous tramadol dosing regimen would provide a Cmax within therange from about 80% to about 125% of the steady-state Cmax and/or Cminof the 50 mg oral tramadol administered every 6 hours. It is especiallypreferred that the steady-state Cmax of the dosing regimen(s) of thepresent invention does not exceed the concentration provided by 50 mgoral tramadol administered every 6 hours, at steady-state by more than15% or more than about 10% (of this range).

In accordance with the present invention, the intravenous tramadoldosing regimens of the present invention and as described herein will besimilar to, not significantly less than, match or exceed the analgesicefficacy of a 50 mg immediate release oral tramadol dose given every 6hours, but may reduce side effects and/or may improve tolerance ascompared to that oral formulation.

The above goals and others are achieved by the present invention,wherein the dose of tramadol is reduced relative to the approved oraldose (50 mg) in the U.S., with the addition of at least one loading doseadministered in a shortened dosing interval as compared to the referencestandard (Ultram® 50 mg oral tablets). By decreasing the dose oftramadol but increasing the number of administrations during the initial24 hour period of tramadol administration, the present inventionachieves the goal of a lowered dose providing similar Cmax, AUC andefficacy as compared to the orally administered 50 mg tramadol Q6 h.

In a preferred embodiment, the dosing regimen comprises 25 mg IVtramadol at hour 0, followed by 25 mg at hour 2, 25 mg at hour 4, and 25mg every 4 hours thereafter (e.g., until the patient no longer requirestreatment with intravenous tramadol). In this embodiment, the maximumplasma concentration (Cmax) of the tramadol rapidly approaches (e.g., atabout 4 hours after the initial intravenous dose, or, e.g., after thethird intravenous dose) the maximum concentration found at steady-statewith respect to a dosing regimen of 50 mg tramadol HCl administeredorally every 6 hours (which steady-state does not occur until about 44hours after the initial oral dose).

The intravenous tramadol formulation in accordance with the inventiontypically includes tramadol in the form of its hydrochloride salt.However, one of ordinary skill in the art will appreciate that otherforms of tramadol may be used, including but not limited to allpharmaceutically acceptable salts of tramadol. Such pharmaceuticallyacceptable salts may include, but are not limited to, metal salts suchas sodium salt, potassium salt, secium salt and the like; alkaline earthmetals such as calcium salt, magnesium salt and the like; organic aminesalts such as triethylamine salt, pyridine salt, picoline salt,ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, sulfate, phosphate and the like;organic acid salts such as formate, acetate, trifluoroacetate, maleate,tartrate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate, and the like; amino acid saltssuch as arginate, asparginate, glutamate and the like.

It is contemplated that with respect to the inventive methods for theintravenous administration of tramadol as described herein, otheranalgesics, preferably opioid analgesics, may be used to treatpostoperative pain in the patient(s), as well. It is particularlycontemplated that one or more opioid analgesics will be administeredpost-surgically to the patient as rescue medicine in order to treatbreakthrough pain that the patient may experience.

The term “opioid analgesic” refers to all drugs, natural or synthetic,with morphine-like actions. The synthetic and semi-synthetic opioidanalgesics are derivatives of five chemical classes of compound:phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; andbenzomorphans, all of which are within the scope of the term. Opioidanalgesics which are useful in the present invention include all opioidagonists or mixed agonist-antagonists, partial agonists, including butnot limited to alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propoxyphene,sufentanil, tilidine, mixtures of any of the foregoing, salts of any ofthe foregoing, and the like.

In certain preferred embodiments, opioid analgesics include morphine,oxycodone, codeine, dihydrocodeine, diacetylmorphine, hydrocodone,hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine,butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine,propoxyphene and pentazocine or pharmaceutically acceptable saltsthereof. In certain preferred embodiments, the opioid agonist ismorphine. Equianalgesic doses of these opioids are generally known tothose persons having ordinary skill in the art.

In certain embodiments, the patient's need for additional analgesictreatment beyond the intravenous tramadol may be ascertained via the useof a surrogate measure of pain. Pain rating scales are used in dailyclinical practice to measure pain intensity. The commonly usedmeasurement scales include the Visual Analog Scale (VAS), the GraphicRating Scale (GRS), the Simple Descriptor Scale (SDS), the NumericalRating Scale (NRS), and the Faces Rating Scale (FRS). All of thesescales have been documented as being valid measures of pain intensity.The three scales most commonly used in the U.S. are the numerical, wordand faces scales. One preferred pain rating scale is the visual analogscale (VAS), a 10 cm. vertical or horizontal line with word anchors atthe extremes, such as “no pain” on one end and “pain as bad as it couldbe” at the other. The patient is asked to make a mark along the line torepresent pain intensity.

Alternatively, the graphic rating scale (GRS) is a variation of thevisual scale which adds words or numbers between the extremes. Wordingadded might include “no pain”, “mild”, “severe”. The descriptor scale(SDS) is a list of adjectives describing different levels of painintensity. For example pain intensity may be described as “no pain”,“mild”, “moderate” or “severe”. The numerical pain rating scale (NPRS)refers to a numerical rating of 0 to 10 or 0 to 5 or to a visual scalewith both words and numbers. The patient is asked to rate the pain with0 being no pain and 10 being the worst possible pain. The faces scalewas developed for use with children. This scale exists in severalvariations but relies on a series of facial expressions to convey painintensity. Grouping patients' rating of pain intensity as measured witha numerical scale ranging from 0 to 10 into categories of mild,moderate, and severe pain is useful for informing treatment decisions,and interpreting study outcomes. In 1995, Serlin and colleagues (Pain,1995, 277-84) developed a technique to establish the cut points formild, moderate, and severe pain by grading pain intensity and functionalinference. Since then, a number of studies have been conducted tocorrelate the numerical scales, for example the NPRS, with cutpointsrelated to levels of pain intensity. Common severity cutpoints are (1 to4) for mild pain, (5 to 6) for moderate pain, and (7 to 10) for severepain.

Surrogate measures of opioid efficacy (analgesia) include sedation,respiratory rate and/or pupil size (via pupillometry), and visualanalogue scale (“VAS”) for “drug effect”. The Sum of Pain IntensityDifferences (SPED) through 48 hours post first dose (SPID48) at rest maybe used as a primary measure of efficacy.

The intravenous tramadol dosing regimens of the invention may be used inthe in the hospital or day hospital setting and therefore administeredby medical staff. The tramadol hydrochloride injection for intravenoususe and its dosing regimen can fill an important need in addition totramadol (e.g., ULTRAM®) tablets and tramadol (e.g., ULTRAM® ER)extended-release tablets by providing this safe and effective injectableanalgesic with a novel mechanism of action (μ-opioid agonist andmonoaminergic reuptake inhibition) for use in the acute post-operativesetting. These dosing regimens may be used, e.g., for all types ofsurgery, including orthopedic surgery (e.g., total knee replacement,bunionectomy) or soft tissue surgery (e.g., elective abdominoplasty).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

This invention is further illustrated by the following examples thatshould not be construed as limiting. Those of skill in the art ofpharmaceutical formulation will readily appreciate that certainmodifications to the examples may be readily effected. Any methods,materials, or excipients which are not particularly described will begenerally known and available those skilled in the drug design and assayand pharmacokinetic analysis.

Example 1

In Example 1, a pharmacokinetic (PK) study in healthy volunteers wasconducted to evaluate the relative exposure of two intravenous (IV) doseregimens of tramadol compared to the approved 100 mg Q6 h oral doseregimen of tramadol. The two tramadol IV dosing regimens were based onvarious pharmacokinetic (PK) simulations done prior to the study, and itwas determined that the following were appropriate for evaluation: (1)75 mg IV REGIMEN: IV tramadol 75 mg administered at Hour 0, followed by75 mg at Hour 3 and Hour 6, and 75 mg every 6 hours thereafter throughHour 42; (2) 50 mg IV REGIMEN: IV tramadol 50 mg administered at Hour 0,followed by 50 mg at Hour 2, 50 mg at hour 4, and 50 mg every 4 hoursthereafter through Hour 44. These two IV dosing regimens were studied ina multiple-dose, randomized, PK 3-way crossover study in 18 healthyvolunteers, each of whom also received 100 mg oral tramadol given every6 hours during one of the periods through Hour 42.

Examination of the parent (tramadol) as well as the primary metabolite(M1 (O-desmethyltramadol) was performed over the 48-hour treatmentperiod. A focus of the analysis was on assessment of Cmax values (toensure the Cmax for the IV formulation was similar to that of the oralformulation) as well as on early concentrations during the first doses(to ensure adequate medication would be provided during the initial 6 to12 hours of treatment as the drugs reached steady-state concentrations).Overall exposure to tramadol was estimated from average trough plasmaconcentrations.

A fitted curve was obtained because the second oral peak was notmeasured in the study. For the modeling portion of the analysis, avalidated Phoenix® WinNonlin® program version 6.4 (Certara) was used forPK analysis, simulation, graphics, tables and statistical calculations.Tramadol plasma concentration-time data observed over the initial 24hours was fit to a linear 1-compartment model with first-orderabsorption and a lag time. For purposes of nonlinear regression, thedata were weighted as 1/observed. Predicted concentration-time data werecalculated based on the individual fitted PK parameters. The oral Cmaxand AUC values over the initial 12 and 24 hours after administration wascalculated using noncompartmental analysis of the predictedconcentration using a fitted model.

Mean plasma tramadol concentrations just after administration (forexample at 3, 6, and 42 h) were higher after 75 mg IV q6 h compared tothe administration of 50 mg IV q4 h and 100 mg PO q6 h. As evidencedfrom the trough/pre-dose samples between 24 and 42 h, the meantranomadol concentrations were very similar for 50 mg IV q4 h and 100 mgPO q6 h but somewhat lower for 75 mg IV q6 h.

The mean tramadol concentrations for 50 mg IV q4 h and 100 mg PO q6 hwere almost superimposable at the end of the pharmacokinetic samplingperiod, between approximately 44 and 48 h, suggesting that the tworegimens provided similar steady-state concentrations (including troughand Cmax concentrations). The mean plasma O-desmethyltramadolconcentrations were higher for 75 mg IV q6 h following the 3rd dose at 6h, but there was appreciable overlap of the trough concentrations for 75mg IV q6 h and 50 mg IV q4 h between 24 and 42 h. The pre-doseconcentrations as well as the concentrations after the last dose at 42 hwere higher for 100 mg PO q6 h compared to both IV arms, presumably dueto first pass metabolism which results in a higher fraction of theactive metabolite in systemic circulation after oral administration.

Select pharmacokinetic parameters (overall Cmax, Cmax at steady-state,trough at steady-state, AUC over the last dosing interval for eachregimen, ie, AUC_(tau n)) for tramadol are summarized in Table 1 below.

TABLE 1 Additional Plasma Pharmacokinetic Parameters of Tramadol 75 mgIV 50 mg IV 100 mg Oral Parameter n Mean SD CV % n Mean SD CV % n MeanSD CV % C_(max) (ng/mL) 14 932 199 21.30 14 736 152 20.60 17 701 17825.44 C_(max(42-48)) (ng/mL) 14 827 234 28.24 — — — — 17 701 178 25.44C_(max(44-48)) (ng/mL) — — — — 14 711 152 21.40 — — — — T₄₈ (ng/mL) 14354 85.9 24.31 14 448 131 29.36 17 497 144 29.09 Css (ng/mL) 14 506 10120.03 14 557 131 23.60 17 579 150 25.96

Exposure to O-desmethyltramadol was higher after 100 mg PO q6 h comparedto either IV treatment, 50 mg IV q4 h or 75 mg IV q6 h. This wasexpected, considering the first pass metabolism after oraladministration. Although exposure parameters were slightly higher for 75mg IV q6 h compared to 50 mg IV q4 h through early time points, exposureto O-desmethyltramadol was comparable for the two IV regimens when theentire pharmacokinetic sampling period was considered. For example, themean Css for O-desmethyltramadol was 86.6 ng/mL for 75 mg IV q6 h and88.9 ng/mL for 50 mg IV q4 h; the mean Css for 100 mg PO q6 h washigher, at 128 ng/mL. This is understandable taking into account thesimilarity in the total IV doses administered in the study (650 mg forthe 50 mg IV q4 h arm, 675 mg for the 75 mg IV q6 h arm) and theslightly higher oral dose (800 mg for the 100 mg PO q6 h arm).

The observed mean (STD) tramadol plasma concentration versus time curvefor IV 50 mg and oral 100 mg as well as the fitted curve for the oral100 mg for the initial 12 hours after administration was obtainedbecause the second oral peak was not measured in the study. The modelfit was very good, with the curve demonstrating the concentrations ofthe IV 50 mg regimen are generally higher after the Hour 2 dose. The 50mg IV regimen was very close to steady-state after the 3rd dose, due tothe loading dose strategy (comparable Cmax after the hour 4 dose to Cmaxafter the Hour 44 dose), and the oral Cmax was achieved later butreaches a similar level to the 50 mg IV regimen.

Plasma pharmacokinetic parameters for tramadol in Example 5 are setforth in Table 2 below:

TABLE 2 75 mg IV 50 mg IV 100 mg Oral Parameter n Mean SD CV % n Mean SDCV % n Mean SD CV % T_(max) (h) 14 15.93 17.36 108.96 14 30.02 19.8966.27 17 44.03 1.01 2.29 C_(max) (ng/mL) 14 932 199 21.30 14 736 15220.60 17 701 178 25.44 C_(1 h) (ng/mL) 14 361 63.8 17.65 14 243 45.218.56 17 278 77.0 27.72 C₂ (ng/mL) — — — — 14 203 31.6 15.59 — — — — C₃(ng/mL) 14 237 41.6 17.53 — — — — — — — — C₆ (ng/mL) — — — — — — — — 17197 55.0 27.93 T_(max(0-2)) (h) — — — — 14 0.54 0.22 40.34 — — — —C_(max(0-2)) (ng/mL) — — — — 14 294 68.5 23.27 — — — — T_(max(0-3)) (h)14 0.50 0.28 55.47 — — — — — — — — C_(max(0-3)) (ng/mL) 14 484 155 31.93— — — — — — — — T_(max(0-6)) (h) — — — — — — — — 17 1.54 0.33 21.60C_(max(0-6)) (ng/mL) — — — — — — — — 17 377 68.9 18.31 T_(max(2-4)) (h)— — — — 14 2.36 0.13 5.40 — — — — C_(max(2-4)) (ng/mL) — — — — 14 47977.7 16.23 — — — — T_(max(3-6)) (h) 14 3.31 0.11 3.19 — — — — — — — —C_(max(3-6)) (ng/mL) 14 756 141 18.65 — — — — — — — — T_(max(42-48)) (h)14 42.38 0.19 0.45 — — — — 17 44.03 1.01 2.29 C_(max(42-48)) (ng/mL) 14827 234 28.24 — — — — 17 701 178 25.44 T_(max(44-48)) (h) — — — — 1444.30 0.11 0.24 — — — — C_(max(44-48)) (ng/mL) — — — — 14 711 152 21.40— — — — C₄₈ (ng/mL) 14 354 85.9 24.31 14 448 131 29.36 17 497 144 29.09AUC_(tau 1) (h * ng/mL) 14 1251 165.4 13.22 15 624.2 85.06 13.64 17 1494282.3 18.90 AUC₀₋₂₄ (h * ng/mL) 14 9932 1958 19.72 14 9520 2106 22.12 177491 1936 25.85 AUC₂₄₋₄₈ (h * ng/mL) 14 9402 2511 26.71 14 11020 285225.88 17 11650 3387 29.07 AUC₀₋₄₈ (h * ng/mL) 14 19330 4427 22.90 1420540 4906 23.89 17 19140 5172 27.02 AUC_(tau n) (h * ng/mL) 14 3036608.3 20.04 14 2228 525.6 23.60 17 3475 902.2 25.97 RAC (C_(max)) 141.7828 0.4975 27.91 14 2.4663 0.4953 20.08 17 1.8588 0.2858 15.37RAC_((trough)) 14 1.5026 0.3613 24.05 14 2.1937 0.4768 21.74 17 2.55800.4577 17.89 RAC (AUC_(tau)) 14 2.4314 0.4060 16.70 14 3.5359 0.466213.18 17 2.3211 0.3437 14.81 Css (ng/mL) 14 506 101 20.03 14 557 13123.60 17 579 150 25.96 P/T Ratio First 14 2.0658 0.6131 29.68 14 1.45660.2812 19.31 17 1.9824 0.3664 18.48 P/T Ratio Last 14 2.3692 0.509021.48 14 1.6370 0.2655 16.22 17 1.4400 0.2286 15.87

Plasma pharmacokinetic parameters of the O-desmethyltramadol metabolitein the study of Example 1 are set forth in Table 3:

TABLE 3 75 mg IV 50 mg IV 100 mg Oral Parameter n Mean SD CV % n Mean SDCV % n Mean SD CV % T_(max) (h) 14 32.99 16.50 50.01 14 44.95 1.59 3.5317 43.97 1.12 2.54 C_(max) (ng/mL) 14 99.2 25.6 25.85 14 96.6 24.5 25.3517 146 37.4 25.62 C_(1 h) (ng/mL) 14 19.9 6.65 33.32 14 11.8 4.57 38.8217 41.4 19.7 47.47 C₂ (ng/mL) — — — — 14 16.9 6.47 38.32 — — — — C₃(ng/mL) 14 29.5 10.0 33.87 — — — — — — — — C₆ (ng/mL) — — — — — — — — 1742.3 13.6 32.19 T_(max(0-2)) (h) — — — — 14 1.85 0.19 10.34 — — — —C_(max(0-2)) (ng/mL) — — — — 14 17.1 6.46 37.91 — — — — T_(max(0-3)) (h)14 2.71 0.49 18.03 — — — — — — — — C_(max(0-3)) (ng/mL) 14 29.7 10.234.28 — — — — — — — — T_(max(0-6)) (h) — — — — — — — — 17 2.04 0.8742.42 C_(max(0-6)) (ng/mL) — — — — — — — — 17 60.3 22.7 37.60T_(max(2-4)) (h) — — — — 14 3.95 0.00 0.00 — — — — C_(max(2-4)) (ng/mL)— — — — 14 37.8 15.5 40.86 — — — — T_(max(3-6)) (h) 14 5.81 0.52 8.98 —— — — — — — — C_(max(3-6)) (ng/mL) 14 59.4 18.6 31.34 — — — — — — — —T_(max(42-48)) (h) 14 43.10 0.36 0.84 — — — — 17 43.97 1.12 2.54C_(max(42-48)) (ng/mL) 14 96.7 25.1 25.99 — — — — 17 146 37.4 25.62T_(max(44-48)) (h) — — — — 14 45.31 0.68 1.50 — — — — C_(max(44-48))(ng/mL) — — — — 14 96.2 24.5 25.46 — — — — C₄₈ (ng/mL) 14 75.9 22.429.48 14 81.7 20.2 24.68 17 111 31.5 28.33 AUC_(tau 1) (h * ng/mL) 14108.3 35.79 33.06 15 39.93 15.89 39.77 17 272.1 97.32 35.77 AUC₀₋₂₄ (h *ng/mL) 14 1608 428.2 26.63 14 1425 405.4 28.44 17 1655 476.6 28.79AUC₂₄₋₄₈ (h * ng/mL) 14 1896 524.5 27.66 14 2002 514.9 25.72 17 2693750.0 27.85 AUC₀₋₄₈ (h * ng/mL) 14 3504 931.2 26.58 14 3427 889.9 25.9717 4349 1139 26.20 AUC_(tau n) (h * ng/mL) 15 519.8 142.7 27.45 14 355.689.39 25.14 17 768.4 209.4 27.26 RAC (C_(max)) 14 3.4575 0.8063 23.32 146.0794 1.4574 23.97 17 2.7316 1.2718 46.56 RAC_((trough)) 14 2.72370.7000 25.70 14 5.2872 1.4637 27.68 17 2.7839 1.0135 36.41 RAC(AUC_(tau)) 14 5.0884 1.2051 23.68 14 9.7100 2.6019 26.80 17 3.12871.5078 48.19 Css (ng/mL) 14 86.6 23.8 27.44 14 88.9 22.3 25.14 17 12834.9 27.25 P/T Ratio First 14 1.0049 0.0185 1.84 14 1.0122 0.0327 3.2317 1.3982 0.1890 13.52 P/T Ratio Last 14 1.2878 0.1073 8.33 14 1.17820.0772 6.55 17 1.3302 0.1635 12.29 M/P Ratio C_(1h) 14 0.0571 0.023240.64 14 0.0503 0.0224 44.54 17 0.1579 0.0798 50.54 M/P Ratio T₄₈ 140.2266 0.0796 35.14 14 0.2002 0.0794 39.67 17 0.2423 0.0929 38.33

The term “STD” as used herein means standard deviation. The term “C₂”means plasma concentration of tramadol at time 2 or hour 2 (in otherwords, the tramadol plasma concentration at 2 hours after the firstadministered tramadol dose). The term “C₃” means plasma concentration oftramadol at time 3 or hour 3 (in other words, the tramadol plasmaconcentration at 3 hours after the first administered tramadol dose).The term “C6” as used herein means plasma concentration of tramadol attime 6 or hour 6 (in other words, the tramadol plasma concentration at 6hours after the first administered tramadol dose). The term “C₄₈” asused herein means plasma concentration of tramadol at time 48 or hour 48(in other words, the tramadol plasma concentration at 48 hours after thefirst administered tramadol dose). The term “C_(ss)” means steady-stateconcentration. The term “C_(max)” means maximum concentration. The term“AUC” means area under the curve. The term “AUC_(tau)” means area underthe plasma concentration-time curve over the dosing interval. As opposedto AUC_((0-inf)) which is extrapolated out to infinity, AUC_(tau n) isthe AUC in the last dosing interval (for example, with respect to the 50mg dosing regimen, that would be at 44-48 hours from first dose). Theterm “RAC” means ratio of accumulation from first dose to steady-state.(Thus, if a patient had a C_(max) of 500 ng/ml in the first interval,and 1000 ng/mL at steady-state, the RAC is 1000/500=2.0). The term “PIT”means peak to trough. The term “M/P” means metabolite to parent(tramadol) ratio.

The mean tramadol C_(max) for the first dose ranged from 294 ng/mL after50 mg IV (C_(max(0-2))) to 484 ng/mL after 75 mg IV (C_(max(0-3))); theC_(max) after the first 100 mg PO (C_(max(0-6))) was 377 ng/mL. Over theentire pharmacokinetic sampling period, the C_(max) for 75 mg IV q6 hwas somewhat higher, 932 ng/mL, compared to the other treatments. TheC_(max) after 50 mg IV q4 h and 100 mg PO q6 h were similar, at 736ng/mL and 701 ng/mL, respectively. Of particular note, the C_(max) atsteady-state for 50 mg IV was 711 ng/ml, while for the oral dose it was701 ng/mL.

The higher peak concentrations for 75 mg IV q6 h was reflected in thefluctuation between the peak and trough concentration; the P/T Ratiosfor the first and last doses of 75 mg IV q6 h were larger (2.0658 to2.3692) than those observed for 50 mg IV q4 h (1.4566 to 1.6370) and 100mg PO q6 h (1.4400 to 1.9824). This result was expected, consideringlonger 6-hour dosing interval for the 75 mg IV treatment, compared tothe 50 mg IV treatment, and more time for drug elimination prior tosubsequent dosing.

During the last 24-hour sampling period (AUC₂₄₋₄₈), the exposure totramadol after 100 mg PO q6 h (11650 h*ng/mL) was comparable to thatafter 50 mg IV q4 h (11020 h*ng/mL); the AUC₂₄₋₄₈ for 75 mg IV q6 h wassomewhat lower (9932 h*ng/mL). Two additional AUCs were calculated atthe time of pharmacokinetic analysis, AUC_(tau 1) (the AUC during thefirst dosing interval) and AUC_(tau n) (the AUC during the last dosinginterval). AUC_(tau 1) and AUC_(tau n) were used to provide anothermeasure of the accumulation during multiple dosing. AUC_(tau n) was usedto characterize the exposure at steady-state during a consistentregimen. Although AUC_(tau n) cannot be compared directly across alltreatments, due to the different dosing intervals of 4 or 6 h, theseAUCs can be used to estimate systemic exposure over a given multiple ofthese intervals, such as 12 h. The predicted exposure over 12 h atsteady state was comparable for 50 mg IV q4 h (3×2228=6684 h*ng/mL) and100 mg PO q6 h (2×3475=6950 h*ng/mL), but somewhat lower for 75 mg IV q6h (2×3036=6072 h*ng/mL). These values correlate well with the averageconcentration at steady-state (Css), at 557 ng/mL and 579 ng/mL for 50mg IV q4 h and 100 mg PO q6 h, respectively, and 506 ng/mL for 75 mg IVq6 h.

The accumulation factors for tramadol ranged from 1.5026 to 2.4314 for75 mg IV q6 h, from 2.1937 to 3.5359 for 50 mg IV q4 h, and from 1.8588to 2.5580 for 100 mg PO q6 h. Overall, these values are in goodagreement with the theoretical accumulation factors of 1.82 for a 6-hdosing interval and 2.42 for a 4-h dosing interval, calculated as1/[1−exp(ln 2*tau/T_(1/2))] and using T_(1/2) of approximately 5.2 h).The shorter dosing interval results in a higher degree of accumulationat steady-state, relative to the concentrations observed after the firstdose, but less fluctuation in the concentrations during the dosinginterval.

The 75 mg IV/100 mg PO ratios ranged from 74.67 to 137.94%, indicatinghigher exposure to tramadol after 75 mg IV q6 h compared to 100 mg PO q6h in general, most apparent through 24 hours. Based on the 80.00-125.00%acceptance criteria for the 90% confidence intervals, AUC₀₋₄₈ was notsignificantly different between these treatments. The 50 mg IV/100 mg POratios ranged from 89.82 to 127.81%, and only AUC₀₋₂₄ had 90% confidenceintervals outside the 80.00-125.00% range; C_(max), AUC₂₄₋₄₈, AUC₀₋₄₈,and T₄₈ were not significantly different between these treatments. The75 mg IV/50 mg IV ratios ranged from 83.13 to 129.16%; although the AUCswere not significantly different across these treatments, the C_(max)and T₄₈ concentrations were, reflecting the more pronounced fluctuationin tramadol concentrations for the 75 mg IV q6 h arm.

Exposure to O-desmethyltramadol was higher after 100 mg PO q6 h comparedto either IV treatment, 50 mg IV q4 h or 75 mg IV q6 h. This wasexpected, considering the first pass metabolism after oraladministration. Although exposure parameters were slightly higher for 75mg IV q6 h compared to 50 mg IV q4 h through early time points, exposureto O-desmethyltramadol was comparable for the two IV regimens when theentire pharmacokinetic sampling period was considered. For example, themean Css for O-desmethyltramadol was 86.6 ng/mL for 75 mg IV q6 h and88.9 ng/mL for 50 mg IV q4 h; the mean Css for 100 mg PO q6 h washigher, at 128 ng/mL. This is understandable taking into account thesimilarity in the total IV doses administered in the study (650 mg forthe 50 mg 1V q4 h arm, 675 mg for the 75 mg IV q6 h arm) and theslightly higher oral dose (800 mg for the 100 mg PO q6 h arm).

The following conclusions are drawn from Example 1: (1) the 50 mg IVregimen, as compared to the 75 mg IV regimen, resulted in less peak totrough fluctuation with lower Cmax. This regimen also provided apharmacokinetic profile very similar to the 100 mg oral dose regimen;and (2) exposure to O-desmethyltramadol was higher after 100 mg PO q6 hcompared to either IV treatment, 50 mg IV or 75 mg IV regimens, based onAUC and Cmax values; (3) overall Cmax was comparable between the 50 mgIV and 100 mg PO regimens; exposure at steady-state to tramadol, basedon Cmax and AUC, was also comparable between 50 mg IV q4 h and 100 mg POq6 h; (4) administration of a lower IV dose more frequently, as in the50 mg IV q4 h regimen compared to the 75 mg IV q6 regimen, resulted inless fluctuation during the dosing interval and a pharmacokineticprofile very similar to the 100 mg oral dose; (5) compared to the 50 mgIV q4 h and 100 mg PO q6 h regimens, greater peak to trough variance intramadol concentrations was observed for the 75 mg IV q6 h regimen. Thedata from Example 1 demonstrate that the 50 mg IV dosing regimen (withtramadol 50 mg at Hour 0, followed by 50 mg at Hour 2, 50 mg at hour 4,and 50 mg every 4 hours thereafter through Hour 44) provides a Cmax andAUC that is similar to the steady-state Cmax and AUC of an oral dose of100 mg tramadol HCl administered every six hours.

Example 2

This invention is further described below with respect to dataprospectively generated as set forth below. Example 2 depicts a 25 mgintravenous dose of tramadol 25 mg at Hour 0, followed by 25 mg tramadolat Hour 2, 25 mg tramadol at hour 4, and 25 mg tramadol every 4 hoursthereafter through Hour 44. The 25 mg IV dose plasma concentrations andpharmacokinetic parameters were based on data generated in Example 1,assuming dose proportionality from the 50 mg IV dose and a % CV whichindependent of magnitude. The software used are plots ofplasma-concentration vs. time for both tramadol and o-desmethyltramadolcreated in Phoenix WinNonlin 6.4. Tables were generated using bothMicrosoft Word and Excel.

Table 4 provides plasma pharmacokinetic parameters of intravenoustramadol 25 mg dosing regimen.

TABLE 4 25 mg IV Parameter n Mean SD CV % T_(max) (h) 14 30.02 19.8966.27 C_(max) (ng/mL) 14 368 76 20.60 C_(1h) (ng/mL) 14 122 23 18.56 T₂(ng/mL) 14 102 16 15.59 T₃ (ng/mL) — — — — T₆ (ng/mL) — — — —T_(max(0-2)) (h) 14 0.54 0.22 40.34 C_(max(0-2)) (ng/mL) 14 147 34 23.27T_(max(0-3)) (h) — — — — C_(max(0-3)) (ng/mL) — — — — T_(max(0-6)) (h) —— — — C_(max(0-6)) (ng/mL) — — — — T_(max(2-4)) (h) 14 2.36 0.13 5.40C_(max(2-4)) (ng/mL) 14 240 39 16.23 T_(max(3-6)) (h) — — — —C_(max(3-6)) (ng/mL) — — — — T_(max(42-48)) (h) — — — — C_(max(42-48))(ng/mL) — — — — T_(max(44-48)) (h) 14 44.3 0.11 0.24 C_(max(44-48))(ng/mL) 14 356 76 21.40 T₄₈ (ng/mL) 14 224 66 29.36 AUC_(tau 1) (h *ng/mL) 15 312 43 13.64 AUC₀₋₂₄ (h * ng/mL) 14 4760 1053 22.12 AUC₂₄₋₄₈(h * ng/mL) 14 5510 1426 25.88 AUC₀₋₄₈ (h * ng/mL) 14 10270 2453 23.89AUC_(tau n) (h * ng/mL) 14 1114 263 23.6 RAC(C_(max)) 14 2.4663 0.495320.08 RAC_((trough)) 14 2.1937 0.4768 21.74 RAC(AUC_(tau)) 14 3.53590.4662 13.18 Css (ng/mL) 14 279 66 23.60 P/T Ratio First 14 1.45660.2812 19.31 P/T Ratio Last 14 1.637 0.2655 16.22

Table 5 provides plasma pharmacokinetic parameters ofO-desmethyltramadol for the dosing regimen of Example 2.

TABLE 5 25 mg IV Parameter n Mean SD CV % T_(max) (h) 14 44.95 1.59 3.53C_(max) (ng/mL) 14 48.3 12.3 25.35 C_(1h) (ng/mL) 14 5.9 2.3 38.82 T₂(ng/mL) 14 8.5 3.2 38.32 T₃ (ng/mL) — — — — T₆ (ng/mL) — — — —T_(max(0-2)) (h) 14 1.85 0.19 10.34 C_(max(0-2)) (ng/mL) 14 8.6 3.237.91 T_(max(0-3)) (h) — — — — C_(max(0-3)) (ng/mL) — — — — T_(max(0-6))(h) — — — — C_(max(0-6)) (ng/mL) — — — — T_(max(2-4)) (h) 14 3.95 0 0C_(max(2-4)) (ng/mL) 14 18.9 7.8 40.86 T_(max(3-6)) (h) — — — —C_(max(3-6)) (ng/mL) — — — — T_(max(42-48)) (h) — — — — C_(max(42-48))(ng/mL) — — — — T_(max(44-48)) (h) 14 45.31 0.68 1.50 C_(max(44-48))(ng/mL) 14 48.1 12.3 25.46 T₄₈ (ng/mL) 14 40.9 10.1 24.68 AUC_(tau 1)(h * ng/mL) 15 20.0 7.9 39.77 AUC₀₋₂₄ (h * ng/mL) 14 712.5 202.7 28.44AUC₂₄₋₄₈ (h * ng/mL) 14 1001.0 257.5 25.72 AUC₀₋₄₈ (h * ng/mL) 14 1713.5445.0 25.97 AUC_(tau n) (h * ng/mL) 14 177.8 44.7 25.14 RAC(C_(max)) 146.0794 1.4574 23.97 RAC_((trough)) 14 5.2872 1.4637 27.68 RAC(AUC_(tau))14 9.71 2.6019 26.80 Css (ng/mL) 14 44.5 11.2 25.14 P/T Ratio First 141.0122 0.0327 3.23 P/T Ratio Last 14 1.1782 0.0772 6.55 M/P RatioC_(1 h) 14 0.0503 0.0224 44.54 M/P Ratio T₄₈ 14 0.2002 0.0794 39.67

Example 3

This invention is further described below in an alternate embodimentwith respect to data prospectively generated as set forth below. Example3 depicts a 25 mg intravenous dose of tramadol 25 mg at Hour 0, followedby 50 mg tramadol at Hour 2, 25 mg tramadol at hour 4, and 25 mgtramadol every 4 hours thereafter through Hour 44.

FIG. 1 provides a mean plasma concentration-time profile (linear scale)for intravenous tramadol administered at a dose of 25 mg at Hour 0,followed by 50 mg at Hour 2, 25 mg at hour 4, and 25 mg every 4 hoursthereafter through Hour 44; and comparatively provides a mean plasmaconcentration-time profile (linear scale) for intravenous tramadoladministered at a dose of 50 mg at Hour 0, followed by 50 mg at Hour 2,50 mg at hour 4, and 50 mg every 4 hours thereafter through Hour 44.FIG. 2 provides a mean plasma concentration-time profile (log scale) forintravenous tramadol administered at a dose of 25 mg at Hour 0, followedby 50 mg at Hour 2, 25 mg at hour 4, and 25 mg every 4 hours thereafterthrough Hour 44; and comparatively provides a mean plasmaconcentration-time profile (log scale) for intravenous tramadoladministered at a dose of 50 mg at Hour 0, followed by 50 mg at Hour 2,50 mg at hour 4, and 50 mg every 4 hours thereafter through Hour 44.FIG. 3 provides a mean plasma concentration-time profile (linear scale)for O-Desmethyltramadol when intravenous tramadol is administered at adose of 25 mg at Hour 0, followed by 50 mg at Hour 2, 25 mg at hour 4,and 25 mg every 4 hours thereafter through Hour 44; and comparativelyprovides a mean plasma concentration-time profile (linear scale) forintravenous tramadol administered at a dose of 50 mg at Hour 0, followedby 50 mg at Hour 2, 50 mg at hour 4, and 50 mg every 4 hours thereafterthrough Hour 44. FIG. 4 provides a mean plasma concentration-timeprofile (log scale) for O-Desmethyltramadol when intravenous tramadol isadministered at a dose of 25 mg at Hour 0, followed by 50 mg at Hour 2,25 mg at hour 4, and 25 mg every 4 hours thereafter through Hour 44; andcomparatively provides a mean plasma concentration-time profile (logscale) for intravenous tramadol administered at a dose of 50 mg at Hour0, followed by 50 mg at Hour 2, 50 mg at hour 4, and 50 mg every 4 hoursthereafter through Hour 44.

Table 6 provides summary statistics concerning plasma concentrations oftramadol 25 mg IV of Example 2 (with a 50 mg loading dose at hour 2) ascompared to tramadol 50 mg IV administered as set forth above. Table 7provides summary statistics concerning plasma concentrations forO-Desmethyltramadol when tramadol 25 mg is administered intravenously asset forth in Example 2 (with a 50 mg loading dose at hour 2) as comparedto plasma concentrations for O-Desmethyltramadol when tramadol 50 mg IVadministered as set forth above.

TABLE 6 Tramadol 25 mg IV Dose Concentrations 50 mg IV DoseConcentrations Time Mean SD Mean SD (hr) N (ng/mL) (ng/mL) CV % N(ng/mL) (ng/mL) CV % 0.00 17 0.3629 1.084 299 17 0.7259 2.169 299 0.15017 77.76 30.20 39 17 155.5 60.40 39 0.250 17 126.6 51.82 41 17 253.1103.6 41 0.500 17 130.5 41.34 32 17 261.0 82.69 32 0.750 17 121.4 35.6029 17 242.9 71.20 29 1.00 17 115.4 33.79 29 17 230.8 67.59 29 1.50 17105.0 29.13 28 17 210.0 58.25 28 2.00 17 94.12 26.58 28 17 188.2 53.1528 2.25 17 234.1 37.88 16 17 468.3 75.76 16 2.50 17 221.0 32.29 15 17442.1 64.58 15 4.00 17 167.7 23.31 14 17 335.4 46.62 14 4.25 17 330.961.10 18 17 661.7 122.2 18 4.50 17 295.9 42.97 15 17 591.8 85.94 15 5.0017 263.6 38.56 15 17 527.3 77.12 15 6.00 17 216.5 39.26 18 17 433.178.52 18 8.00 17 173.2 36.61 21 17 346.4 73.22 21 12.0 17 176.6 45.65 2617 353.1 91.30 26 16.0 17 194.1 53.08 27 17 388.2 106.2 27 20.0 17 209.662.28 30 17 419.2 124.6 30 24.0 17 206.7 55.99 27 17 413.4 112.0 27 32.017 211.0 54.86 26 17 422.1 109.7 26 40.0 17 211.8 65.69 31 17 423.6131.4 31 44.0 17 211.8 53.61 25 17 423.6 107.2 25 44.3 17 348.4 75.04 2217 696.8 150.1 22 44.5 17 327.4 66.46 20 17 654.7 132.9 20 44.8 17 322.462.83 19 17 644.8 125.7 19 45.0 17 305.0 59.86 20 17 610.0 119.7 20 45.517 276.5 60.75 22 17 553.1 121.5 22 46.0 17 264.0 61.61 23 17 527.9123.2 23 47.0 17 244.8 65.76 27 17 489.5 131.5 27 48.0 17 216.8 61.35 2817 433.6 122.7 28

TABLE 7 O-Desmethyltramadol 25 mg IV Dose Concentrations 50 mg IV DoseConcentrations Time Mean SD Mean SD (hr) N (ng/mL) (ng/mL) CV % N(ng/mL) (ng/mL) CV % 0.00 17 0.03618 0.1492 412 17 0.07235 0.2983 4120.150 17 0.1898 0.2705 143 17 0.3796 0.5410 143 0.250 17 0.7798 0.541669 17 1.560 1.083 69 0.500 17 3.429 1.704 50 17 6.858 3.408 50 0.750 174.702 2.089 44 17 9.405 4.179 44 1.00 17 5.855 2.729 47 17 11.71 5.45847 1.50 17 7.504 3.288 44 17 15.01 6.576 44 2.00 17 8.304 3.763 45 1716.61 7.527 45 2.25 17 9.787 4.493 46 17 19.57 8.986 46 2.50 17 12.996.090 47 17 25.98 12.18 47 4.00 17 18.67 8.020 43 17 37.35 16.04 43 4.2517 19.92 7.970 40 17 39.84 15.94 40 4.50 17 23.63 9.819 42 17 47.2619.64 42 5.00 17 25.89 9.825 38 17 51.78 19.65 38 6.00 17 27.77 10.15 3717 55.54 20.29 37 8.00 17 27.90 9.712 35 17 55.79 19.42 35 12.0 17 32.899.979 30 17 65.77 19.96 30 16.0 17 36.29 10.37 29 17 72.58 20.74 29 20.017 37.39 10.81 29 17 74.78 21.62 29 24.0 17 38.76 11.13 29 17 77.5222.26 29 32.0 17 38.76 11.52 30 17 77.51 23.04 30 40.0 17 42.45 11.66 2717 84.91 23.31 27 44.0 17 42.08 11.40 27 17 84.15 22.80 27 44.3 17 42.9711.57 27 17 85.95 23.13 27 44.5 17 44.93 12.23 27 17 89.86 24.46 27 44.817 45.11 12.43 28 17 90.22 24.87 28 45.0 17 46.51 12.06 26 17 93.0224.11 26 45.5 17 45.36 11.65 26 17 90.73 23.31 26 46.0 17 44.93 11.60 2617 89.86 23.20 26 47.0 17 43.12 11.29 26 17 86.24 22.57 26 48.0 17 40.4110.28 25 17 80.81 20.55 25

Example 4

Example 4 is a multiple dose, steady-state dose proportionality study oftramadol injection 50 mg and 100 mg administered intravenously andtramadol 50 mg and 100 mg (Ultram® tablet) administered orally in 32healthy volunteers. The primary objective of the study was to establishthe comparative bioavailability of tramadol 50 mg and 100 mg (Ultram®tablet) administered orally at steady-state relative to tramadolinjection 50 mg and 100 mg administered intravenously and to establishthe doses proportionality of tramadol injection at steady-state. Thepurpose of including this study in the present application is to providedata for the 50 mg tramadol oral dose as compared to the simulatedtramadol intravenous data provided in Examples 2 and 3. The study was anopen-label, single-period, randomized, parallel treatment design.Subjects received study drug every 6 hours beginning on the morning ofDay 1 and ending on the morning of Day 3. The first dose on Day 1 andthe last dose on Day 3 were administered after a minimum 10 hour fast.Tramadol injection was administered intravenously over 15 minutes.Tramadol injection was diluted in 50 mL of normal saline and a pump wasused to standardize the administration of the injection. Tramadoltablets were administered with 240 mL of water. Blood samples foranalysis of tramadol and O-desmethyltramadol (M1) plasma concentrationswere obtained pre-dose (within 5 minutes prior to study drugadministration) for each of the 9 doses. On day 3, blood samples werealso obtained at 0.083 (5 min), 0.17 (10 min) 0.25, 0.5, 0.75, 1, 1.25,1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12 18, 24 36 and 48 hours after thelast dose of study drug. The primary variables were the C_(max) and AUC₆of tramadol (oral and IV) and M1 following the last dose.

The results for tramadol are provided in Table 8 below:

TABLE 8 Tramadol Tramadol Tramadol Dosed as 50 mg Tramadol Dosed as 100gm Dosed as 50 mg Oral Dosed as 100 mg Oral IV Mean ± Mean ± SD IV Mean± Mean ± SD Parameter Units SD (CV %) (CV %) SD (CV %) (CV %) C_(max)ng/mL 541 ± 126 355 ± 121 1250 ± 236  703 ± 210 (23.4%) (34.1%) (18.6%)(29.9%) C_(min) ng/mL 203 ± 50  213 ± 93  539 ± 172 405 ± 151 (24.6%)(43.7%) (32.0%) (37.4%) T_(max) h 0.375 ± 0.189 1.88 ± 0.78 0.406 ±0.442 2.32 ± 1.35 (50.4%) (41.6%) (108.8%) (58.2%) AUC₆ ng · h/mL 1968 ±453  1731 ± 625  4732 ± 1239 3365 ± 1009 (23.0%) (36.1%) (26.2%) (30.0%)AUC_(t) ng · h/mL 4011 ± 1047 4363 ± 2027 11184 ± 4271  8662 ± 4258(26.1%) (46.5%) (38.2%) (49.2%) AUC_(∞) ng · h/mL 4038 ± 1060 4453 ±2111 11432 ± 4542  8851 ± 4572 (26.3%) (47.4%) (39.7%) (51.6%)Trough/Peak Ratio 0.387 ± 0.088 0.585 ± 0.091 0.430 ± 0.106 0.578 ±0.154 (22.8%) (15.5%) (24.5%) (26.6%)

The results for the tramadol M1 metabolite are provided in Table 9below:

TABLE 9 Tramadol Tramadol Tramadol Dosed as 50 mg Tramadol Dosed as 100gm Dosed as 50 mg Oral Dosed as 100 mg Oral IV Mean ± Mean ± SD IV Mean± Mean ± SD Parameter Units SD (CV %) (CV %) SD (CV %) (CV %) C_(max)ng/mL 78.6 ± 12.4 100 ± 30  165 ± 48  130 ± 39  (15.8%) (30.0%) (29.0%)(29.7%) C_(min) ng/mL 55.9 ± 7.4  65.9 ± 15.8 130 ± 37  93.6 ± 34.6(13.3%) (24.0%) (28.7%) (37.0%) T_(max) h 1.53 ± 0.57 2.44 ± 1.59 1.59 ±1.04 2.25 ± 1.14 (37.5%) (65.3%) (65.5%) (50.7%) AUC₆ ng · h/mL 398 ±59  508 ± 139 904 ± 278 700 ± 223 (14.8%) (27.3%) (30.7%) (31.9%)AUC_(t) ng · h/mL 1086 ± 149  1454 ± 401  2733 ± 1040 2084 ± 740 (13.7%) (27.6%) (38.1%) (35.5%) AUC_(∞) ng · h/mL 1100 ± 150  1489 ±409  2844 ± 1187 2126 ± 739  (13.6%) (27.5%) (41.7%) (34.8%) Trough/ratio^(a) 0.715 ± 0.044 0.670 ± 0.061 0.795 ± 0.040 0.707 ± 0.080 Peak (6.1%)  (9.1%)  (5.0%) (11.3%)

Comparing the results set forth in Table 8 to the Cmax results in Table4 and FIG. 1, it can be seen that the mean tramadol concentration forthe intravenous dosing regimen provides similar steady-state peak andtrough concentrations (see) as compared to a dosing regimen of 50 mgtramadol HCl administered orally every 6 hours at steady-state.

CONCLUSION

All patents and publications identified in the above paragraphs arehereby incorporated by reference in their entireties. It will be readilyapparent to one of ordinary skill in the relevant arts that othersuitable modifications and adaptations to the methods and applicationsdescribed herein are suitable and may be made without departing from thescope of the invention or any embodiment thereof. While the inventionhas been described in connection with certain embodiments, it is notintended to limit the invention to the particular forms set forth, buton the contrary, it is intended to cover such alternatives,modifications and equivalents as may be included within the spirit andscope of the invention as defined by the following claims. All of thepatents and publications cited herein are hereby incorporated byreference.

What is claimed is:
 1. A method of administering tramadol for treating acute pain in human patients via an intravenous dosing regimen comprising intravenously administering a first dose of tramadol to a human patients in an amount of about 25 mg; intravenously administering a second dose of tramadol to the human patients in an amount of about 25 mg at about 2 hours after the first dose; intravenously administering a third dose of tramadol to the human patients in an amount of about 25 mg at about 2 hours after the second dose; and thereafter intravenously administering additional doses of tramadol to the human patients in an amount of about 25 mg tramadol at dosage intervals of about 4 hours, until the patient no longer requires treatment with intravenous tramadol, wherein the tramadol is tramadol base or a pharmaceutically acceptable salt of tramadol.
 2. The method of claim 1, wherein the human patients are suffering from acute post-operative pain.
 3. The method of claim 1, wherein a therapeutically effective dose of an intravenous opioid analgesic is administered to the patients (i) at the end of the surgery or (ii) if the human patients request analgesia before the second dose of tramadol.
 4. The method of claim 1, further comprising orally administering about 50 mg to about 100 mg tramadol to the human patients about every 6 hours after the human patients no longer require treatment with intravenous tramadol, until the human patients no longer require treatment with oral tramadol, wherein the tramadol is tramadol base or a pharmaceutically acceptable salt of tramadol.
 5. The method of claim 1, wherein the dosing regimen provides a Cmax after the third intravenous dose of tramadol 25 mg, and the Cmax of the intravenous dosing regimen after the third intravenous dose of tramadol 25 mg is similar to the steady-state Cmax achieved with an oral tramadol dose of 50 mg administered every 6 hours.
 6. The method of claim 1, wherein the intravenous dosing regimen provides a Cmax and AUC of tramadol which is similar to the Cmax and AUC of an oral dose of 50 mg tramadol HCl given every 6 hours at steady-state.
 7. The method of claim 6, wherein such that the intravenous dosing regimen provides a Cmax of tramadol at steady-state from about 80% to about 125% of about 368 ng/mL.
 8. The method of claim 7, wherein the dosing regimen provides a Cmin at steady-state, and the Cmin of tramadol at steady-state via this intravenous dosing regimen is from about 80% to about 125% of about 224 ng/ml.
 9. The method of claim 2, wherein the dosing regimen provides a Cmax after the third intravenous dose of tramadol 25 mg, and the Cmax of the intravenous dosing regimen after the third intravenous dose of tramadol 25 mg is similar to the steady-state Cmax achieved with an oral tramadol dose of 50 mg administered every 6 hours.
 10. The method of claim 2, wherein the intravenous dosing regimen provides a Cmax and AUC of tramadol which is similar to the Cmax and AUC of an oral dose of 50 mg tramadol HCl given every 6 hours at steady-state.
 11. The method of claim 10, wherein such that the intravenous dosing regimen provides a Cmax of tramadol at steady-state from about 80% to about 125% of about 368 ng/mL.
 12. The method of claim 11, wherein the dosing regimen provides a Cmin at steady-state, and the Cmin of tramadol at steady-state via this intravenous dosing regimen is from about 80% to about 125% of about 224 ng/ml.
 13. The method of claim 9, wherein a therapeutically effective dose of an intravenous opioid analgesic is administered to the patients at the end of the surgery.
 14. The method of claim 9, further comprising orally administering about 50 mg to about 100 mg tramadol to the human patients about every 6 hours after the human patients no longer requires treatment with intravenous tramadol, until the human patients no longer require treatment with oral tramadol, wherein the tramadol is tramadol base or a pharmaceutically acceptable salt of tramadol.
 15. The method of claim 9, wherein a therapeutically effective dose of an intravenous opioid analgesic is administered to the patients (i) at the end of the surgery or (ii) if the human patients request analgesia before the second dose of tramadol.
 16. A method of administering tramadol for treating acute pain in human patients via an intravenous dosing regimen comprising intravenously administering a first dose of tramadol to human patients in an amount of about 25 mg; intravenously administering a second dose of tramadol to the human patients in an amount of about 25 mg at about 2 hours after the first dose; intravenously administering a third dose of tramadol to the human patients in an amount of about 25 mg at about 2 hours after the second dose; and thereafter intravenously administering additional doses of tramadol to the human patients in an amount of about 25 mg tramadol at dosage intervals of about 4 hours, until the patients no longer require treatment with intravenous tramadol, wherein the tramadol is tramadol base or a pharmaceutically acceptable salt of tramadol and a reduction in at least one side-effect associated with tramadol therapy selected from the group consisting of nausea, vomiting, and seizure is achieved.
 17. The method of claim 16, wherein the human patients are suffering from acute post-operative pain.
 18. The method of claim 16, wherein the dosing regimen provides a Cmax after the third intravenous dose of tramadol 25 mg, and the Cmax of the intravenous dosing regimen after the third intravenous dose of tramadol 25 mg is similar to the steady-state Cmax achieved with an oral tramadol dose of 50 mg administered every 6 hours.
 19. The method of claim 16, wherein the intravenous dosing regimen provides a Cmax and AUC of tramadol which is similar to the Cmax and AUC of an oral dose of 50 mg tramadol HCl given every 6 hours at steady-state.
 20. The method of claim 16, wherein a therapeutically effective dose of an intravenous opioid analgesic is administered to the patients (i) at the end of the surgery or (ii) if the human patients requests analgesia before the second dose of tramadol. 